Cover image for Vol. 33 Issue 7

Edited By: Jan A. Nolta

Impact Factor: 6.523

ISI Journal Citation Reports © Ranking: 2014: 2/21 (CELL & TISSUE ENGINEERING); 4/68 (Hematology); 10/162 (Biotechnology & Applied Microbiology); 19/211 (Oncology); 32/184 (Cell Biology)

Online ISSN: 1549-4918

All Virtual Issues

To quickly access one of the virtual issues, click on a link from the list below.

Top Ten Articles on the Biology of Embryonic and Induced Pluripotent Stem Cells

Protocols to differentiate and examine embryonic stem cells have improved steadily over the past years, and have given biologists incredible insight into lineage commitment and development. Then the Nobel-prize winning development of induced pluripotent stem cells (iPSCs) from adult cell sources completely changed the field of stem cell biology. With the ability to create and study iPSC lines and their lineage-specific derivatives from patients with known diseases and genotypes, the use of this technology has exploded. In the current issue we present our ten top downloaded manuscripts from Stem Cells in 2014-2015, that focus on the biology of embryonic and induced pluripotent stem cells.

Concise Review: Generation of Neurons From Somatic Cells of Healthy Individuals and Neurological Patients Through Induced Pluripotency or Direct Conversion
Iván Velasco, Patricia Salazar, Alessandra Giorgetti, Verónica Ramos-Mejía, Julio Castaño, Damià Romero-Moya and Pablo Menendez

Modeling Human Retinal Development with Patient-Specific Induced Pluripotent Stem Cells Reveals Multiple Roles for Visual System Homeobox 2
M. Joseph Phillips, Enio T. Perez, Jessica M. Martin, Samantha T. Reshel, Kyle A. Wallace, Elizabeth E. Capowski, Ruchira Singh, Lynda S. Wright, Eric M. Clark, Patrick M. Barney, Ron Stewart, Sarah J. Dickerson, Michael J. Miller, E. Ferda Percin, James A. Thomson and David M. Gamm

Concise Review: A Population Shift View of Cellular Reprogramming
Antonio del Sol and Noel J. Buckley

Retinoic Acid Suppresses the Canonical Wnt Signaling Pathway in Embryonic Stem Cells and Activates the Noncanonical Wnt Signaling Pathway
Kwame Osei-Sarfo and Lorraine J. Gudas

Pluripotent Stem Cells Derived From Mouse Primordial Germ Cells by Small Molecule Compounds
Tohru Kimura, Yoshiaki Kaga, Yoichi Sekita, Keita Fujikawa, Tsunetoshi Nakatani, Mika Odamoto, Soichiro Funaki, Masahito Ikawa, Kuniya Abe and Toru Nakano

Live Fluorescent RNA-Based Detection of Pluripotency Gene Expression in Embryonic and Induced Pluripotent Stem Cells of Different Species
Harald Lahm, Stefanie Doppler, Martina Dreßen, Astrid Werner, Klaudia Adamczyk, Dominic Schrambke, Thomas Brade, Karl-Ludwig Laugwitz, Marcus-André Deutsch, Matthias Schiemann, Rüdiger Lange, Alessandra Moretti and Markus Krane

TET2 Deficiency Inhibits Mesoderm and Hematopoietic Differentiation in Human Embryonic Stem Cells
Thierry Langlois, Barbara da Costa Reis Monte-Mor, Gaëlle Lenglet, Nathalie Droin, Caroline Marty, Jean-Pierre Le Couédic, Carole Almire, Nathalie Auger, Thomas Mercher, François Delhommeau, Jesper Christensen, Kristian Helin, Najet Debili, François Fuks, Olivier A. Bernard, Eric Solary, William Vainchenker and Isabelle Plo

Gremlin 2 Promotes Differentiation of Embryonic Stem Cells to Atrial Fate by Activation of the JNK Signaling Pathway
Vineeta Tanwar, Jeffery B. Bylund, Jianyong Hu, Jingbo Yan, Joel M. Walthall, Amrita Mukherjee, William H. Heaton, Wen-Der Wang, Franck Potet, Meena Rai, Sabina Kupershmidt, Ela W. Knapik and Antonis K. Hatzopoulos

PRMT1 and PRMT8 Regulate Retinoic Acid-Dependent Neuronal Differentiation with Implications to Neuropathology
Zoltan Simandi, Erik Czipa, Attila Horvath, Aron Koszeghy, Csilla Bordas, Szilárd Póliska, István Juhász, László Imre, Gábor Szabó, Balazs Dezso, Endre Barta, Sascha Sauer, Katalin Karolyi, Ilona Kovacs, Gábor Hutóczki, László Bognár, Álmos Klekner, Peter Szucs, Bálint L. Bálint and Laszlo Nagy

Differentiation of Human Induced Pluripotent Stem Cells into Brown and White Adipocytes: Role of Pax3
Tala Mohsen-Kanson, Anne-Laure Hafner, Brigitte Wdziekonski, Yasuhiro Takashima, Phi Villageois, Audrey Carrière, Maria Svensson, Claude Bagnis, Bérengère Chignon-Sicard, Per-Arne Svensson, Louis Casteilla, Austin Smith and Christian Dani

The Best Papers from our 2014 Young Investigators

The STEM CELLS Young Investigator Award honors a young scientist who is principal author of a significant research paper published in STEM CELLS. The STEM CELLS Editors support the efforts of these emerging researchers and encourage the development of these young investigators who are making significant impacts in this field, thus fostering the future of their clinical applications.

Tissue-Specific Stem Cells

In situ mechanotransduction via vinculin regulates stem cell differentiation
Adam Engler

Tissue-Specific Stem Cells

Rx1 Defines Retinal Precursor Identity by Repressing Alternative Fates Through the Activation of TLE2 and Hes4
Martina Giannaccini

Tissue-Specific Stem Cells

Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis
Eva Gonzalez-Suarez

Embryonic Stem Cells/Induced Pluripotent Stem Cells

Dynamic Migration and Cell-Cell Interactions of Early Reprogramming Revealed by High-Resolution Time-Lapse Imaging
Shangqin Guo

Cancer Stem Cells

FoxG1 Interacts with Bmi1 to Regulate Self-Renewal and Tumorigenicity of Medulloblastoma Stem Cells
Sheila Singh

Leukemia, breast and ovarian cancer stem cells

This virtual issue is devoted to leukemia, breast cancer stem cells, and ovarian cancer stem cells. Theoretical aspects of transplantation, analysis of clinical data, and the use of hematopoietic stem cell transplantation in acute myeloid leukemia are discussed. Key aspects of the role of breast cancer stem cells in the pathogenesis of breast cancer are examined in articles devoted to breast cancer initiation, progression, and therapy. Factors affecting intratumoral heterogeneity, invasion, and migration of ovarian cancer cells are examined.

Concise review: Cancer stem cells and minimal residual disease
Ghiaur G, Gerber J, Jones RJ

Concise review: the role of hematopoietic stem cell transplantation in the treatment of acute myeloid leukemia
Hamilton BK, Copelan EA

Focal adhesion kinase splice variants maintain primitive acute myeloid leukemia cells through altered Wnt signaling
Despeaux M, Chicanne G, Rouer E, De Toni-Costes F, Bertrand J, Mansat-De Mas V, Vergnolle N, Eaves C, Payrastre B, Girault JA, Racaud-Sultan C

Lmo2 induces hematopoietic stem cell-like features in T-cell progenitor cells prior to leukemia
Cleveland SM, Smith S, Tripathi R, Mathias EM, Goodings C, Elliott N, Peng D, El-Rifai W, Yi D, Chen X, Li L, Mullighan C, Downing JR, Love P, Dave UP

TEL (ETV6)-AML1 (RUNX1) initiates self-renewing fetal pro-B cells in association with a transcriptional program shared with embryonic stem cells in mice
Tsuzuki S, Seto M

Self-renewal of leukemia stem cells in Friend virus-induced erythroleukemia requires proviral insertional activation of Spi1 and hedgehog signaling but not mutation of p53
Hegde S, Hankey P, Paulson RF

Radiation-induced reprogramming of breast cancer cells
Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F

P-cadherin is coexpressed with CD44 and CD49f and mediates stem cell properties in basal-like breast cancer
Vieira AF, Ricardo S, Ablett MP, Dionisio MR, Mendes N, Albergaria A, Farnie G, Gerhard R, Cameselle-Teijeiro JF, Seruca R, Schmitt F, Clarke RB, Paredes J

Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target
Ginestier C, Monville F, Wicinski J, Cabaud O, Cervera N, Josselin E, Finetti P, Guille A, Larderet G, Viens P, Sebti S, Bertucci F, Birnbaum D, Charafe-Jauffret E

Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway
Yang J, Liao D, Chen C, Liu Y, Chuang TH, Xiang R, Markowitz D, Reisfeld RA, Luo Y

ROCK1 inhibition promotes the self-renewal of a novel mouse mammary cancer stem cell
Castro DJ, Maurer J, Hebbard L, Oshima RG

Intravital imaging of cancer stem cell plasticity in mammary tumors
Zomer A, Ellenbroek SI, Ritsma L, Beerling E, Vrisekoop N, Van Rheenen J

Remodeling of endogenous mammary epithelium by breast cancer stem cells
Parashurama N, Lobo NA, Ito K, Mosley AR, Habte FG, Zabala M, Smith BR, Lam J, Weissman IL, Clarke MF, Gambhir SS

Histone deacetylase inhibitors stimulate dedifferentiation of human breast cancer cells through WNT/beta-catenin signaling
Debeb BG, Lacerda L, Xu W, Larson R, Solley T, Atkinson R, Sulman EP, Ueno NT, Krishnamurthy S, Reuben JM, Buchholz TA, Woodward WA

Phosphosulindac (OXT-328) selectively targets breast cancer stem cells in vitro and in human breast cancer xenografts
Zhu C, Cheng KW, Ouyang N, Huang L, Sun Y, Constantinides P, Rigas B

Targeting p90 ribosomal S6 kinase eliminates tumor-initiating cells by inactivating Y-box binding protein-1 in triple-negative breast cancers
Stratford AL, Reipas K, Hu K, Fotovati A, Brough R, Frankum J, Takhar M, Watson P, Ashworth A, Lord CJ, Lasham A, Print CG, Dunn SE

Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer
Abelson S, Shamai Y, Berger L, Shouval R, Skorecki K, Tzukerman M

Autocrine CCL5 signaling promotes invasion and migration of CD133+ ovarian cancer stem-like cells via NF-kappaB-mediated MMP-9 upregulation
Long H, Xie R, Xiang T, Zhao Z, Lin S, Liang Z, Chen Z, Zhu B

Stem Cells in Regenerative Medicine

In addition to our leading role in understanding the basic mechanisms governing stem cell function over the past 32 years, STEM CELLS is proud to contribute key information toward the rapidly expanding field of regenerative medicine.

The current virtual collection of the Editor’s picks in this field over the past year contain reports of key stem cell clinical trials, important information about how stem cells respond to and regulate their environment after transplantation, and reports of matrices that can be implanted to attract and guide resident, endogenous stem cells.

For other important reports on the translation of therapies from the basic mechanisms toward clinical therapies please visit the website for our “sister journal” Stem Cells Translational Medicine. Enjoy!

Jan A. Nolta

Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double-blind, Randomized, Placebo-Controlled Trial
Kyunghoon Min, Junyoung Song, Jin Young Kang, Jooyeon Ko, Ju Seok Ryu, Myung Seo Kang, Su Jin Jang, Sang Heum Kim, Doyeun Oh, Moon Kyu Kim, Sung Soo Kim and MinYoung Kim

Injectable bone tissue engineering using expanded mesenchymal stem cells
Yamada Y, Nakamura S, Ito K, Umemura E, Hara K, Nagasaka T, Abe A, Baba S, Furuichi Y, Izumi Y, Klein OD, Wakabayashi T.

Biomaterial Microenvironments to Support the Generation of New Neurons in the Adult Brain
Anthony Conway and David V. Schaffer

Intra-Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A Proof-of-Concept Clinical Trial
Chris Hyunchul Jo, Young Gil Lee, Won Hyoung Shin, Hyang Kim, Jee Won Chai, Eui Cheol Jeong, Ji Eun Kim, Hackjoon Shim, Ji Sun Shin, Il Seob Shin, Jeong Chan Ra, Sohee Oh and Kang Sup Yoon

Bone Marrow Mesenchymal Stromal Cells to Treat Tissue Damage in Allogeneic Stem Cell Transplant Recipients: Correlation of Biological Markers with Clinical Responses
Fang Yin, Minoo Battiwalla, Sawa Ito, Xingmin Feng, Fariba Chinian, Jan Joseph Melenhorst, Eleftheria Koklanaris, Marianna Sabatino, David Stroncek, Leigh Samsel, Jeffrey Klotz, Nancy F. Hensel, Pamela G. Robey and A. John Barrett

Concise Review: Spinal Cord Injuries: How Could Adult Mesenchymal and Neural Crest Stem Cells Take Up the Challenge?
Virginie Neirinckx, Dorothée Cantinieaux, Cécile Coste, Bernard Rogister, Rachelle Franzen and Sabine Wislet-Gendebien

Concise Review: The Immune Status of Mesenchymal Stem Cells and Its Relevance for Therapeutic Application
Shoshan Knaän-Shanzer

Priming with Ligands Secreted by Human Stromal Progenitor Cells Promotes Grafts of Cardiac Stem/Progenitor Cells After Myocardial Infarction
Yoshitaka Iso, Krithika S. Rao, Charla N. Poole, A. K. M. Tarikuz Zaman, Ingrid Curril, Burton E. Sobel, Jan Kajstura, Piero Anversa and Jeffrey L. Spees

Brief Report: Reconstruction of Joint Hyaline Cartilage by Autologous Progenitor Cells Derived from Ear Elastic Cartilage
Mitsuru Mizuno, Shinji Kobayashi, Takanori Takebe, Hiroomi Kan, Yuichiro Yabuki, Takahisa Matsuzaki, Hiroshi Y. Yoshikawa, Seiichiro Nakabayashi, Lee Jeong Ik, Jiro Maegawa and Hideki Taniguchi

Concise Review: Current Status of Stem Cells and Regenerative Medicine in Lung Biology and Diseases
Daniel J. Weiss

Concise Review: Hurdles in a Successful Example of Limbal Stem Cell-based Regenerative Medicine
Graziella Pellegrini, Paolo Rama, Antonio Di Rocco, Athanasios Panaras and Michele De Luca

Concise Review: Bridging the Gap: Bone Regeneration Using Skeletal Stem Cell-Based Strategies—Where Are We Now?
Jonathan I. Dawson, Janos Kanczler, Rahul Tare, Moustapha Kassem and Richard O.C. Oreffo

Concise Review: Engineering Myocardial Tissue: The Convergence of Stem Cells Biology and Tissue Engineering Technology
Jan Willem Buikema, Peter Van Der Meer, Joost P.G. Sluijter and Ibrahim J. Domian

Concise review: Combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy
Abderrahim Naji, Nathalie Rouas-Freiss, Antoine Durrbach, Edgardo D. Carosella, Luc Sensébé and Frédéric Deschaseaux

Concise review: Bone marrow autotransplants for liver disease?
Iman Saramipoor Behbahan, Armand Keating and Robert Peter Gale

Costimulation-adhesion blockade is superior to Cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation
Bruno C. Huber, Julia D. Ransohoff, Katherine J. Ransohoff, Johannes Riegler, Antje Ebert, Kazuki Kodo, Yongquan Gong, Veronica Sanchez-Freire, Devaveena Dey, Nigel G. Kooreman, Sebastian Diecke, Wendy Y. Zhang, Justin Odegaard, Shijun Hu, Joseph D. Gold, Robert C. Robbins and Joseph C. Wu

Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn's fistula
Woo Yong Lee, Kyu Joo Park, Yong Beom Cho, Sang Nam Yoon, Kee Ho Song, Do Sun Kim, Sang Hun Jung, Mihyung Kim, Hee-Won Yoo, Inok Kim, Hunjoo Ha and Chang Sik Yu

The Best Papers from Our 2012 Young Investigators

The Best Papers from our 2012 Young Investigators

The STEM CELLS Young Investigator Award honors a young scientist who is principal author of a significant research paper published in STEM CELLS. The STEM CELLS Editors support the efforts of these emerging researchers and encourage the development of these young investigators who are making significant impacts in this field, thus fostering the future of their clinical applications.

Glycogen Synthase Kinase 3β and Activin/Nodal Inhibition in Human Embryonic Stem Cells Induces a Pre-Neuroepithelial State That Is Required for Specification to a Floor Plate Cell Lineage
Denham, Mark

Expression of Heme Oxygenase-1 in Neural Stem/Progenitor Cells as a Potential Mechanism to Evade Host Immune Response
Bonnamain, Virginie

Cell Surface Structures Influence Lung Clearance Rate of Systemically Infused Mesenchymal Stromal Cells
Mathieux, Elodie

Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood?
Nystedt, Johanna

Inhibition of T Cell Protein Tyrosine Phosphatase Enhances Interleukin-18-Dependent Hematopoietic Stem Cell Expansion
von Bahr, Lena

FM19G11 Favors Spinal Cord Injury Regeneration and Stem Cell Self-Renewal by Mitochondrial Uncoupling and Glucose Metabolism Induction
Bourdeau, Annie

Skin-derived Precursors as a Source of Progenitors for Cutaneous Nerve Regeneration
Moreno Manzano

Monoclonal Antibodies Against Lgr5 Identify Human Colorectal Cancer Stem Cells
Le, Lu Q.

Brief Report: Intravital Imaging of Cancer Stem Cell Plasticity in Mammary Tumors
Kemper, Kristel

Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double-blind, Randomized, Placebo-Controlled Trial
Van Rheenen, Jacco


Therapeutic Stem Cells for Cancer Papers

Khalid Shah

Despite the considerable progress that has been made towards developing cancer therapeutics, there is still an urgent need for creating alternate and innovative means of cancer treatment. The most notable pitfalls of current treatments are the short half-life of a number of cancer specific drugs, limited drug delivery to some cancer types, and their adverse effects on vital non-cancerous bodily tissues. For the last decade, increasing number of research groups have focused on developing and testing therapeutic stem cells in different animal models of cancer. The ability of adult mesenchymal stem cells (MSCs) and neural stem cells (NSCs) to preferentially migrate towards local and disseminated malignant disease and interact with different tissue environments present them as attractive candidates for cell based therapies in humans. Recently, induced pluripotent stem cells (iPSCs), which provide a novel and practical tool for human disease modeling and correction, have demonstrated therapeutic potential for cancer treatment.

The unmodified stem cells, particularly MSCs, possess anti-tumor effects both in vitro and in different mouse models of cancer. This is attributed to the factors released by MSCs that have antitumor properties, which can reduce the proliferation of glioma, melanoma, lung cancer, hepatoma, and breast cancer cells. Both MSCs and NSCs have been genetically modified, primarily to introduce and over-express exogenous genes for expression/secretion of a desired therapeutic factor for targeted treatment of both primary and metastatic tumor types. Mesenchymal stem cells (MSCs) are multipotent cells that can be isolated and expanded with relative ease from a number of different sources, including bone marrow, cord blood, adipose tissue, and dental pulp. Although MSCs play a primary role in tissue regeneration, they also have the proven ability to migrate specifically to the site of multiple tumor types in vivo. Although different MSC types have been engineered with therapeutic agents to specifically target numerous tumor types, the ability to image MSC homing to tumors and engraftment in real-time to confirm tumor targeting is essential to increase understanding of this process and facilitate translation to the clinical setting. Dwyer et al (STEM CELLS 2011;29:1149-117) explored the non-invasive tracking of MSC migration and sodium iodide symporter (NIS) transgene expression in real time prior to therapy in a mouse model of breast cancer. A major advantage to this approach is the ability to noninvasively image uptake of a tracer such as 99mTechnetium pertechnetate (99mTcO_4) or 123Iodide (123I) before administration of a therapeutic dose of 131I. Dwyer et al engineered MSCs to express sodium NIS and utilized MSC-NIS for imaging and subsequent therapy of breast cancer. Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC-NIS), followed by (99m) Technetium pertechnetate imaging. SPECT imaging and subsequent bio-distribution studies revealed significant reduction in radionuclide accumulation in non-target tissue as compared to the tumor tissue 2 weeks post MSC-NIS and (131) I injection. Based on imaging/biodistribution data, animals received a therapeutic dose of (131) I 2 weeks after MSC-NIS injection which resulted in a significant reduction in tumor growth. Non-invasive tracking of MSC migration and transgene expression in real time prior to therapy is a major advantage of this study's technique. As MSCs have the ability to target multiple tumor types, this approach has potential applications in a range of cancers.

NSCs isolated from both embryonic and adult human tissues have emerged as attractive candidates for delivering therapeutic proteins that specifically target tumor cells. NSCs can be expanded and manipulated in vitro, and re-engrafted following transplantation. NSCs have shown the ability to migrate extensively to sites of different pathologies and reintegrate into tissue architecture to give rise to progeny consisting of both stem cells and lineage-restricted terminal cell types. Numerous studies have demonstrated the inherent ability of NSCs to seek out and infiltrate invasive tumors and can be used as cellular vehicles for delivering therapeutic proteins to different tumor types like medulloblastoma, melanoma, brain metastases, and disseminated neuroblastoma. NSCs, like MSCs, have been genetically modified to express exogenous genes for targeted treatment of different cancer types. Among these tumor targeting agents, different prodrug activation schemes which convert non-toxic prodrugs into toxic anti-metabolites are available for selective killing of tumor cells. These include cytosine deaminase (CD), herpes simplex virus (HSV)-1, Thymidine kinase (TK), and carboxyesterase genes, which confer sensitivity to 5-fluorocytosine 5-FC, ganciclovir (GCV), and camptothecin-11 (CPT-11), respectively, and are being evaluated in clinical trials. Activation of prodrugs that are non-toxic to NSCs and have a bystander tumor-killing effect are appropriate for the use of NSCs as “pharmacologic pumps”. Zhao et al (STEM CELLS 2012; 30:314-325) show that NSCs preferentially target tumor metastases in multiple organs, including liver, lung, lymph nodes, and femur, versus the primary intramammary fat pad tumor. They also show that increased NSC tropism to breast tumor cell lines is strongly correlated with the invasiveness of cancer cells, and have identified Interleukin 6 (IL-6) as a major cytokine mediating NSC tropism to invasive breast cancer cells (STEM CELLS 2012; 30:314-325). In an effort to explore NSC based therapies in such pre-clinical models, they genetically modified NSCs to secrete rabbit carboxylesterase (rCE), an enzyme that activates the CPT-11 prodrug to SN-38, a potent topoisomerase I inhibitor, to effect tumor-localized chemotherapy. A significant reduction of metastatic tumor burden in lung and lymph nodes was seen post treatment of tumor-bearing mice with NSC-rCE cells, in combination with CPT-11. This study suggests that NSC mediated enzyme/prodrug therapy may be more effective and less toxic than currently available chemotherapy strategies for breast cancer metastases, and warrants further investigation of NSC mediated delivery of targeted therapeutics for advanced metastatic breast cancers.

To realize the full potential of using NSCs for cancer therapeutics, it is desirable to have a reliable and stable supply of human NSCs. Pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are attractive cell sources to derive differentiated cells, including NSCs. Human iPSCs appear to be more attractive for clinical applications since these cells are relatively easy to generate through reprogramming of differentiated somatic cells with transcription factors. This reprogramming procedure circumvents the bioethical controversies associated with the derivation of human ESCs from human embryos. Furthermore, transplantation of the differentiated progeny of iPSCs which are reprogrammed from the patient’s own cells, reduces the likelihood of immune rejection. In a recent study by Yang et al (STEM CELLS 2012;30:1021-1029), iPSCs were derived from primary human fibroblasts and then differentiated into NSCs. These iPS-derived NSC (iPS-NSC) displayed a robust homing to established orthotopic mouse mammary tumors in both immuno-deficient and immuno-competent mice. iPS-NSC engineered to express HSV-TK effectively inhibited the growth of orthotopic 4T1 breast tumor and the metastatic spread of the cancer cells post systemic delivery of prodrug, GCV, resulting in a prolonged survival of the tumor-bearing mice.

Although therapeutically engineered NSCs and MSCs are emerging as a very effective tumor specific therapeutic approach for different cancer types, the assessment of the long-term fate and the eradication of therapeutic SC post-tumor treatment is critical if such promising therapies are to be increasingly translated into clinical practice. Tumor necrosis factor apoptosis inducing ligand (TRAIL) has emerged as a prime candidate for the treatment of several cancers due to its ability to induce apoptosis in a tumor-specific manner. The major interest in TRAIL as an anticancer agent was initiated by early studies in which TRAIL-induced killing was shown in a wide variety of tumor cells in vitro and in vivo, while normal cells were unaffected by TRAIL treatment. A number of studies have shown the therapeutic efficacy of different adult stem cell types, including MSCs, engineered to express TRAIL in either tumor cell lines or mouse models of colorectal carcinoma, gliomas, lung, breast, squamous, and cervical cancer. Martinez-Quintanilla et al (STEM CELLS 2013;31:1706-1714) developed an efficient stem cell based therapeutic strategy that simultaneously allows killing of tumor cells with TRAIL and assessment and eradication of MSCs post-treatment of highly malignant glioblastoma multiforme (GBM) brain tumor, utilizing prodrug converting enzyme, HSV-TK. MSCs engineered to co-express HSV-TK and a potent and secretable variant of TRAIL(S-TRAIL) induced caspase mediated GBM cell death and showed selective MSC sensitization to the prodrug GCV. A significant decrease in tumor growth and a subsequent increase in survival were observed when mice bearing a highly aggressive GBM were treated with MSCs co-expressing S-TRAIL and HSV-TK. Furthermore, the systemic administration of GCV post-tumor treatment selectively eliminated therapeutic MSCs expressing HSV-TK in vitro and in vivo, which was monitored in real time by positron emission-computed tomography (PET) imaging utilizing 18F-FHBG, a substrate for HSV-TK (STEM CELLS 2013;31:1706-1714). This study demonstrates the development and validation of a novel therapeutic/safety strategy that has implications for translating stem cell based therapies into clinics.

The anti-tumor effects of unmodified MSCs have been attributed to the factors released by MSCs that reduce the proliferation of glioma, melanoma, lung cancer, hepatoma, and breast cancer cells. In a recently published study, Nasuno et al (STEM CELLS 2013) studied the therapeutic effect of unmodified MSCs in different models of colon carcinogenesis. The study utilized three different models: an azoxymethane (AOM)/dextran sulfate sodium colitis-associated carcinoma model, an aberrant crypt foci (ACF) model, and a model to assess the acute apoptotic response of a genotoxic carcinogen (AARGC). MSCs were shown to partially cancel the AOM-induced tumor initiation, but not tumor promotion, suggesting that MSCs do not reduce aberrant crypt foci but block ACF formation. AARGC is accepted as one of the in vivo mechanisms that suppresses tumorigenicity. MSCs inhibited AARGC in colonic epithelial cells because of the removal of O6-methylguanine adducts through O6-methylguanine-DNA methyltransferase activation. The anti-carcinogenetic properties of MSCs in vitro required transforming growth factor (TGF)-β signaling because such properties were completely abrogated by absorption of TGF-β under indirect co-culture conditions. MSCs also inhibited AOM-induced tumor initiation by preventing the initiating cells from sustaining DNA insults and subsequently inducing G1 arrest in the initiated cells that escaped AARGC. This study confirms that exogenous unmodified MSCs possess anti-tumor properties. Although a complete mechanistic insight into the properties of MSCs has yet to be achieved, it is clear from this study that MSCs act on tumors by reducing the number of initiating cells and/or to induce G1 arrest in early initiated cells in colon carcinogenesis models.

To conclude, a thorough understanding of stem cell biology and fate in different tumor models which closely recapitulate clinical settings of tumor growth and heterogeneity is critical when developing stem cell based therapies for clinical translation in cancer patients.

Mesenchymal Stem Cell-mediated delivery of the sodium iodide symporter supports radionuclide imaging and treatment of breast cancer.
Dwyer RM, Ryan J, Havelin RJ, Morris JC, Miller BW, Liu Z, Flavin R, O'Flatharta C, Foley MJ, Barrett HH, Murphy JM, Barry FP, O'Brien T, Kerin MJ

Tumor tropism of intravenously injected human-induced pluripotent stem cell-derived neural stem cells and their gene therapy application in a metastatic breast cancer model.
Yang J, Lam DH, Goh SS, Lee EX, Zhao Y, Tay FC, Chen C, Du S, Balasundaram G, Shahbazi M, Tham CK, Ng WH, Toh HC, Wang S

Human neural stem cell tropism to metastatic breast cancer.
Zhao D, Najbauer J, Annala AJ, Garcia E, Metz MZ, Gutova M, Polewski MD, Gilchrist M, Glackin CA, Kim SU, Aboody KS

Mesenchymal stem cells cancel azoxymethane-induced tumor initiation.
Masanao Nasuno, Yoshiaki Arimura, Kanna Nagaishi, Hiroyuki Isshiki, Kei Onodera, Suguru Nakagaki, Shuhei Watanabe, Masashi Idogawa, Kentaro Yamashita, Yasuyoshi Naishiro, Yasushi Adachi, Hiromu Suzuki, Mineko Fujimiya, Kohzoh Imai and Yasuhisa Shinomura

Therapeutic efficacy and fate of bimodal engineered stem cells in malignant brain tumors.
Martinez-Quintanilla J, Bhere D, Heidari P, He D, Mahmood U, Shah K.


Neural Stem Cells Papers

Concise Review: Can Stem Cells be Used to Treat or Model Alzheimer's Disease?
Wesley W. Chen and Mathew Blurton-Jones

Specification of Midbrain Dopamine Neurons from Primate Pluripotent Stem Cells
Jiajie Xi, Yan Liu, Huisheng Liu, Hong Chen, Marina E. Emborg and Su-Chun Zhang

Exosome-Mediated Transfer of miR-133b from Multipotent Mesenchymal Stromal Cells to Neural Cells Contributes to Neurite Outgrowth
Hongqi Xin, Yi Li, Ben Buller, Mark Katakowski, Yi Zhang, Xinli Wang, Xia Shang, Zheng Gang Zhang and Michael Chopp

Human-Induced Pluripotent Stem Cells form Functional Neurons and Improve Recovery After Grafting in Stroke-Damaged Brain
Koichi Oki, Jemal Tatarishvili, James Wood, Philipp Koch, Somsak Wattananit, Yutaka Mine, Emanuela Monni, Daniel Tornero, Henrik Ahlenius, Julia Ladewig, Oliver Brüstle, Olle Lindvall and Zaal Kokaia

Neural Stem Cells Directly Differentiated from Partially Reprogrammed Fibroblasts Rapidly Acquire Gliogenic Competency
Takeshi Matsui, Morito Takano, Kenji Yoshida, Soichiro Ono, Chikako Fujisaki, Yumi Matsuzaki, Yoshiaki Toyama, Masaya Nakamura, Hideyuki Okano and Wado Akamatsu

Concise Review: Stem Cells in the Corneal Stroma
Niveditha Pinnamaneni and James L. Funderburgh

Genome-Wide Analysis of N1ICD/RBPJ Targets In Vivo Reveals Direct Transcriptional Regulation of Wnt, SHH, and Hippo Pathway Effectors by Notch1
Yaochen Li, Matthew Aaron Hibbs, Ashley Lauren Gard, Natalia Aliakseeuna Shylo and Kyuson Yun

Differentiation Efficiency of Induced Pluripotent Stem Cells Depends on the Number of Reprogramming Factors
Matthias Löhle, Andreas Hermann, Hannes Glaß, Andrea Kempe, Sigrid C. Schwarz, Jeong Beom Kim, Claire Poulet, Ursula Ravens, Johannes Schwarz, Hans R. Schöler and Alexander Storch

Nuclear Factor Kappa B Signaling Initiates Early Differentiation of Neural Stem Cells
Yonggang Zhang, Jianjun Liu, Shaohua Yao, Fang Li, Lin Xin, Mowen Lai, Valerie Bracchi-Ricard, Hong Xu, William Yen, Wentong Meng, Shu Liu, Leiting Yang, Shaffiat Karmally, Jin Liu, Hongyan Zhu, Jennifer Gordon, Kamel Khalili, Shanthi Srinivasan, John R. Bethea, Xianming Mo and Wenhui Hu

Nestin- and Doublecortin-Positive Cells Reside in Adult Spinal Cord Meninges and Participate in Injury-Induced Parenchymal Reaction
Ilaria Decimo, Francesco Bifari, Francisco Javier Rodriguez, Giorgio Malpeli, Sissi Dolci, Valentina Lavarini, Silvia Pretto, Sandra Vasquez, Marina Sciancalepore, Alberto Montalbano, Valeria Berton, Mauro Krampera and Guido Fumagalli

Induced Pluripotency - Making Stem Cells For All Reasons

Lyle Armstrong and Majlinda Lako

For the last thirty years science has been fascinated by pluripotent stem cells, a fact underlined by the burgeoning number of Nobel prizes the field. In view of the recent award to Shinya Yamanaka and John Gurdon, we thought an editorial highlighting some of the major reports that have appeared in Stem Cells over the last two years covering various aspects of the study of induced pluripotent stem cells was timely. These cells, which we will refer to as iPSC for the sake of brevity, but also because this is by now an almost universally accepted term, have generated a great deal of enthusiasm because it may be possible at last to generate stem cells specific to the individual patient. This may herald the development of personal medicine at some point in the future but in the meanwhile there are a multitude of applications here and now which make iPSC a valuable research tool, a point underlined by the enormous number of iPSC related publications to appear in recent years.

The pursuit of pluripotent perfection

As with any technology, the early examples of iPSC had serious drawbacks. The first iPSC lines were derived using retroviral or lentiviral vectors that inserted reprogramming transgenes directly into the genome of the target cell. The insertions were random and of indeterminate number which raised questions about the utility of these early iPSC. Naturally, techniques that could either eliminate the reprogramming vectors from the iPSC or even induce pluripotency without having to use viral vectors in the first place were desirable. A recent compromise uses Sendai virus to encode the reprogramming transgenes and since this agent completes its life cycle in the cytoplasm of its target cell, the possibility of integration into the host genome is minimised. Prior to this development, a number of articles appeared in Stem Cells that are worthy of mention. The first of these came from the group of Gustavo Mostoslavsky (STEM CELLS 2010;28:64–74) and showed that it was possible to generate iPSC free of exogenous transgenes using an excisable polycistronic vector. This encoded 3 or 4 reprogramming factors flanked by loxP so that the integrated vector could be removed by highly efficient cre-mediated excision. Further publications confirmed the utility of this vector system (marketed as STEMCCA) especially the derivation of more than 100 transgene free lung disease specific iPSC (STEM CELLS 2010;28:1728–1740). This latter publication reported iPSC from a range of diseases affecting the epithelial, endothelial, or interstitial compartments of the lung, including cystic fibrosis, α-1 antitrypsin deficiency-related emphysema, scleroderma, and sickle-cell disease and as such represents one of the earlier attempts at large scale disease modelling using iPSC. More of this in the next section!
Generating iPSC is inherently inefficient. At best we can reprogram only a small number of the somatic cells selected into bona-fide iPSC colonies, with efficiencies ranging from nearly 1% to very small numbers indeed. With readily available tissues such as fibroblasts from young donors (which grow well) this may not be so important provided that the colonies of prospective iPSC progress to give validated lines in reasonable numbers; however if they do not, then the process of sub-culturing the “failures” until there can be no doubt that they will never develop into useful iPSC can be very time consuming. Methods that increase the efficiency of derivation are therefore useful and Stem Cells has published at least one paper worthy of note in this area (STEM CELLS 2010;28:713–72028:713–720) wherein stimulation with sodium butyrate was shown to enhance the iPSC derivation efficiency up to 200 fold. Application of sodium butyrate could be transient (15- to 51-fold enhancement using either retroviral or piggyBac transposon vectors expressing 4 to 5 reprogramming genes) or long term (>100- to 200-fold on reprogramming in the absence of eitherKLF4 or MYC transgenes) and showed no negative effects on the quality of the iPSC which demonstrated normal karyotypes and expression of genes consistent with pluripotency.

Some disturbing questions

The equivalence of iPSC to embryonic stem cells (hESC) was questioned almost as soon as the first examples of iPSC were reported. Given that they are required to pass the same tests of pluripotency as hESC, there was initial enthusiasm amongst iPSC generating groups that the degree of similarity would be high but this suffered a few setbacks when reports appeared suggesting that iPSC showed a few disturbing differences in their gene expression patterns. This could have been passed off as the result of genetic differences between the individual cell donors from whom the iPSC were generated; after all most of the hESC derivation programmes that preceded iPSC produced relatively few cell lines so we might expect the greater number of iPSC donors to put genetic diversity “in the spotlight”, however a report in Stem Cells in 2010 from Robert Lanza’s group suggested the problems with iPSC might be rather more ominous. This report (STEM CELLS 2010;28:704–712) suggested that while human iPSC were capable of differentiating to a range of somatic cell types (hemangioblasts/blast cells (BCs), endothelial cells, and hematopoietic cells with phenotypic and morphologic characteristics similar to those derived from hESCs) they only did so with much reduced efficiency. That in itself was not so bad but the report further stated that some types of cells (vascular endothelial cells and retinal pigmented epithelium) began to senesce after their first population doubling, implying, much to the concern of many iPSC investigators, that some cells differentiated from iPSC might be of limited clinical use. This prompted investigations in our own group into the biochemical background of iPSC to determine if they had the same ability to defend their genomes against environmental insults as hESC which are able to defend their genomic integrity by maintaining low levels of reactive oxygen species (ROS) through a combination of enhanced removal capacity and limited production of these molecules. Data published in Stem Cells in 2010 (STEM CELLS 2010;28:661–673) indicated that not only do iPSC posses very similar mechanisms for the removal of ROS, they also have eliminated many of the mitochondria present in the donor fibroblasts to generate iPSC with similar mitochondrial mass to hESC. This was thought to be an important pre-requisite allowing iPSC to adopt a more glycolytic ATP synthesis system which was shown in another report (STEM CELLS 2010;28:721–733) to be an important part of the reprogramming process needed to re-establish pluripotency. Moreover, the latter publication addressed the question of mitochondrial function in iPSC in some detail. The mitochondria of hESC appear to function quite differently to those of differentiated, somatic cells (Faucho-Oliveira et al J Cell Sci. 2007 Nov 15;120(Pt 22):4025-34.) so it was important to show that the functional capacity of iPSC mitochondria reverted to a state consistent with the pluripotent phenotype. Furthermore, since mitochondria show an enhanced tendency to accumulate age related changes, there was (and still is) considerable interest in the stem cell community to show if iPSC were able to reverse or eliminate these harmful alterations. The reports of Prigione et al (STEM CELLS 2010;28:721–733 and STEM CELLS 2011; 29:1338–1348) demonstrate that somatic mitochondria within human iPSCs revert to an immature ESC-like state with respect to their sub-cellular distribution, morphology, DNA content and biochemical characteristics. These parameters were reversible upon differentiation of the iPSC in a parallel manner to that observed for hESC. Interestingly, the presence of mutations in the mitochondrial DNA of somatic cells did not appear to affect their ability to reprogram into iPSC however it was of some concern that some iPSC appeared to have acquired mitochondrial mutations not present in the original donor fibroblasts. Most of these mutations were not of the type that could have caused disease states normally associated with homoplasmic or heteroplasmic mitochondrial substitutions, insertions or deletions but the report did highlight the value of screening newly derived iPSC for the presence of mutations that might have more serious downstream consequences if cell replacement therapies were an objective of their derivation. An inability to remove existing mitochondrial mutations is perhaps not surprising since the epigenetic reprogramming required for iPSC generation will be unlikely to influence the mitochondrial genome. The process by which excess fibroblast mitochondria are eliminated is not clearly understood but it may be just a simple matter of restricting mitochondrial biogenesis and allowing the existing numbers to be progressively diluted during expansion of iPSC numbers from a small group of reprogramming cells. If this is true, the presence of mutated mitochondrial DNA in individual iPSC will be a random selection and we will need to screen several iPSC lines to find ones that have eliminated the mutated copies (or at least reduced them to harmless levels) especially in iPSC derived from older individuals. The appearance of new mutations in iPSC is more disturbing and increases the importance of screening.

Modelling and correcting disease

Apart from the early senescence of some iPSC derived somatic cell type (which was only one observation that has been challenged by other groups e.g. Gokoh et al Cell Reprog 2011, 13(4): 361-70)) they do seem to be quite similar to hESC and are probably sufficiently so to allow development of in vitro models of certain genetic diseases and in some cases the development of differentiated cells that may be therapeutic options for such diseases. Several reports have appeared in Stem Cells over the last two years that underline this possibility quite effectively.
Parkinson’s disease affects significant numbers of individuals and places a large burden upon the healthcare systems of many nations. The dysfunctional cell type in this condition is mostly accepted as the dopaminergic neurons of the substantia nigra and it has been suggested that replacing these with healthy counterparts generated in vitro from iPSC is one option for treating the disease. In view of this, a report from Xianmin Zeng (STEM CELLS2010;28:1893–1904) at the Buck Institute of Ageing showed that dopaminergic neurons can be generated efficiently from human iPSC using methods similar to those applied to hESC for the same purpose. The resulting dopaminergic neurons were functional and improved behavioral deficits in 6-hydroxydopamine-lesioned rats after transplantation. It will be some while before procedures of this type can be approved for human application but reports of this type encourage us to believe that iPSC technology is suitable for treating disease. Moreover, dopaminergic neurons obtained from Parkinson’s disease patients may be used to generate neurons that are valuable investigative tools for increasing our understanding of the causes of the disease and the screening of small molecules that have an impact on its progression. This is a particularly valuable undertaking since we can potentially apply vast numbers of prospective drugs to populations of disease specific and control neurons without having to test them on human subjects. This is an increasingly popular approach to conducting molecule library screening and hit-to-lead efficacy / toxicity trials that is expected to reduce the time needed to bring new medical entities to market.
Diseases such as Parkinson’s disease are thought to result from complex interactions at the molecular level and there may be involvement of multiple genes in the process. It is even possible that there may be no direct involvement of mutated genes that cause the necessary molecular changes and it may simply be that some individuals are more susceptible to the environmental stresses that are thought to contribute to dopaminergic neuron loss. Complex traits such as this are difficult to address and although it is possible to use iPSC derived from large numbers of patients and controls to examine the impact of polymorphisms (for example) on disease susceptibility, it is much simpler to investigate diseases resulting from single gene mutations. It is also more likely that we will be able to correct these mutations and produce “repaired” iPSC for subsequent differentiation into clinically transplantable cell types. A poignant example of this was reported in Stem Cells in November 2011 (STEM CELLS 2011;29:1717–1726) and described the application of zinc finger nuclease (ZNF) technology to affect gene correction in iPSC lines derived from sufferers of sickle cell anemia. The technique succeeds because engineered ZNFs substantially increase the frequency of homologous recombination in human pluripotent cells. Gene correction by homologous recombination and by ZFNs requires a single cell suspension to achieve a high enough transfection efficiency to ensure that enough cells have accepted the gene targeting construct. Human pluripotent cells do not respond well to separation into single cells and most of these are unable to form colonies afterwards so in addition to the already poor efficiency of homologous recombination, the probability of obtaining gene corrected pluripotent stem cell colonies is very low. Techniques such as ZNFs increase these numbers to manageable levels so the single cell issue is less problematic. In addition, ZFN techniques have more specific integration into the target gene
Not all therapies envisage the transplantation of cells directly into organ regions such the substantia nigra or the bone marrow in the case of the sickle cell work. Some prospective applications call for engineering of biocompatible structures ex vivo for surgical implantation into the body and this is the basis of the science of tissue engineering. iPSC have enormous potential in this area since they may act as a source of somatic cell needed to build new organs such as cartilage or bone. An important publication in Stem Cells in February 2011 (STEM CELLS 2011;29:206–216) demonstrated the practicality of growing osteoblasts derived from iPSC (in the case from mouse iPSC) in a 3D scaffold made from gelatine. These data demonstrate functional osteoblast differentiation from iPS cells both in vitro and in vivo and reveal a source of cells, which merit evaluation for their potential uses in orthopedic medicine and understanding of molecular mechanisms of orthopedic disease

To conclude, the last two years have been highly productive for the iPSC research field. The pharmaceutical industry is beginning to show significant interest in these fascinating and versatile cells for hit to lead studies as described earlier which in turn has resulted in some large funding awards aimed at generating the considerable numbers of iPSC lines needed to model complex diseases. Prime examples of this are the MRC funded derivation programme at the Sanger Centre, Cambridge, UK and the European StemBANNC consortium. The future is looking bright indeed for iPSC.

Hemangioblastic Derivatives from Human Induced Pluripotent Stem Cells Exhibit Limited Expansion and Early Senescence
Feng, Q; Lu, SJ; Klimanskaya, I; Gomes, I; Kim, D; Chung, Y; Honig, GR; Kim, KS; Lanza, R

Butyrate Greatly Enhances Derivation of Human Induced Pluripotent Stem Cells by Promoting Epigenetic Remodeling and the Expression of Pluripotency-Associated Genes
Mali, P; Chou, BK; Yen, J; Ye, ZH; Zou, JZ; Dowey, S; Brodsky, RA; Ohm, JE; Yu, WN; Baylin, SB; Yusa, K; Bradley, A; Meyers, DJ; Mukherjee, C; Cole, PA; Cheng, LZ

The Senescence-Related Mitochondrial/Oxidative Stress Pathway is Repressed in Human Induced Pluripotent Stem Cells
Prigione, A; Fauler, B; Lurz, R; Lehrach, H; Adjaye, J

Excision of Reprogramming Transgenes Improves the Differentiation Potential of iPS Cells Generated with a Single Excisable Vector
Sommer, CA; Sommer, AG; Longmire, TA; Christodoulou, C; Thomas, DD; Gostissa, M; Alt, FW; Murphy, GJ; Kotton, DN; Mostoslavsky, G

Generation of Transgene-Free Lung Disease-Specific Human Induced Pluripotent Stem Cells Using a Single Excisable Lentiviral Stem Cell Cassette
Somers, A; Jean, JC; Sommer, CA; Omari, A; Ford, CC; Mills, JA; Ying, L; Sommer, AG; Jean, JM; Smith, BW; Lafyatis, R; Demierre, MF; Weiss, DJ; French, DL; Gadue, P; Murphy, GJ; Mostoslavsky, G; Kotton, DN

Efficient Generation of Functional Dopaminergic Neurons from Human Induced Pluripotent Stem Cells Under Defined Conditions
Swistowski, A; Peng, J; Liu, QY; Mali, P; Rao, MS; Cheng, LZ; Zeng, XM

In Vitro High-Capacity Assay to Quantify the Clonal Heterogeneity in Trilineage Potential of Mesenchymal Stem Cells Reveals a Complex Hierarchy of Lineage Commitment
Russell, KC; Phinney, DG; Lacey, MR; Barrilleaux, BL; Meyertholen, KE; O'Connor, KC

Human Induced Pluripotent Stem Cells Develop Teratoma More Efficiently and Faster Than Human Embryonic Stem Cells Regardless the Site of Injection
Gutierrez-Aranda, I; Ramos-Mejia, V; Bueno, C; Munoz-Lopez, M; Real, PJ; Macia, A; Sanchez, L; Ligero, G; Garcia-Parez, JL; Menendez, P

Human Induced Pluripotent Stem Cell Lines Show Stress Defense Mechanisms and Mitochondrial Regulation Similar to Those of Human Embryonic Stem Cells
Armstrong, L; Tilgner, K; Saretzki, G; Atkinson, SP; Stojkovic, M; Moreno, R; Przyborski, S; Lako, M

In Situ Genetic Correction of the Sickle Cell Anemia Mutation in Human Induced Pluripotent Stem Cells Using Engineered Zinc Finger Nucleases
Sebastiano, V; Maeder, ML; Angstman, JF; Haddad, B; Khayter, C; Yeo, DT; Goodwin, MJ; Hawkins, JS; Ramirez, CL; Batista, LFZ; Artandi, SE; Wernig, M; Joung, JK

Osteoblasts Derived from Induced Pluripotent Stem Cells Form Calcified Structures in Scaffolds Both in Vitro and in Vivo
Bilousova, G; Jun, DH; King, KB; De Langhe, S; Chick, WS; Torchia, EC; Chow, KS; Klemm, DJ; Roop, DR; Majka, SM

Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell-like Metabolic Reprogramming
Prigione, A; Lichtner, B; Kuhl, H; Struys, EA; Wamelink, M; Lehrach, H; Ralser, M; Timmermann, B; Adjaye, J

MSCs for What Ails You

Mark Pittenger

There is no shortage of exciting research on mesenchymal stem cells, also known as multipotential stromal cells and mesenchymal stromal cells, or MSCs for short. Over the last decade, there have been more than 10,000 papers published on many aspects of MSC biology and potential clinical use. The proliferation of publications itself can be a barrier to entering and understanding this promising field. Nevertheless, the brave of heart will find reward in the intriguing and thought provoking publications on MSCs and approaches to use them therapeutically that are representative of the field of stem cell biology in general. We thought it appropriate to highlight some reports on MSCs that have appeared in the pages of Stem Cells over the past two years.

MSCs for treating inflammation and immune responses
One of the most useful traits of MSCs is their ability to curtail the inflammatory response caused by tissue damage, infection or immune recognition. Relatively small numbers of MSCs infused locally or systemically have the ability to reduce inflammation in many tissues. The nature of this anti-inflammatory effect has been attributed to soluble factors, of which 11 have been identified and carefully described in the last decade including transforming growth factor β (TGFβ), hepatocyte growth factor (HGF), prostaglandin E2 (PGE2), interleukin 1 receptor antagonist (IL-1Rag), IL-6, IL-10, inducible nitric oxide synthetase (iNOS), galectin-1 (Gal-1), TNFα induced protein-6 (TSG-6), indoleamine 2,3-dioxygenase (IDO) and human leukocyte antigen G (HLA-G). The ongoing production of these factors by MSCs at the site of inflammation likely leads to effective local concentrations, although more distant systemic effects may be at play as well. Recent work has examined the anti-inflammatory role played by MSCs in patients with ischemic stroke (Lee et al SC-10-0027.R1), in animal studies of acute kidney injury (Morigi et al), in acute lung injury (reviewed by Lee et al SC-10-1173.R2), in animal studies of lung fibrosis (Majka et al), in reduction of neuropathy in a mouse model of Krabbe’s disease (Bunnell et al and Sousa et al), in reduction of amyloid plaques in an Alzheimer disease model (Bae et al), in conversion of macrophages to anti-inflammatory M2 type (Le et al SC-10-0542.R1) and in colitis (Duijvestein et al ), and inflammatory bowel disease (Menedez et al).

The MSC anti-inflammatory effects are of interest in tissue and organ transplantation, including pancreatic islet transplantation (Sordi et al) and Stojkovic and colleagues have reviewed the use of MSCs for the complications of diabetes such as retinopathy, cardiomyopathy, neuropathy, nephropathy and diabetic wounds (Stojkovic et al). While most of these tissue effects may be attributable to the inhibition of inflammatory TH1 cells, this would seem to open the body to excessive TH2 mediated allergic effects or bacterial colonization. However, this seems to not be the case as a recent report described the inhibition of the allergic reaction in the airways of mice by MSCs (Goodwin et al) and several reports have shown that MSCs may be beneficial in treating sepsis. For example, Matthay and colleagues (Matthay et al) has described experiments were MSCs reduced the bacterial loads in lung and the authors attributed this antibacterial effect to the secretion of the LL-37 peptide by MSCs.

Pre-treatment, Pre-differentiation and De-differentiation
While implanted MSCs readily differentiate to certain lineages, it always appears there are many fewer differentiating to the desired lineage than expected. This is due to a number of factors, some known and some unknown. It is known that MSCs implanted attached on a matrix in a bone environment readily form new bone, so adherence to matrices and a favorable mesenchymal environment enhances MSC performance in this setting. Pioglitizone is an insulin sensitizer under study largely for diabetes but has found its way into the MSC field where pretreatment of MSCs with pioglitizone improved their in vitro expression of cardiac proteins, their engraftment in infarcted rat hearts, and the left ventricular ejection fraction- a measure of heart function- of the damaged hearts compared to those hearts receiving untreated MSCs (Shinmura et al). Similarly, pretreatment of MSCs with the angiotensin receptor antagonist candesartan resulted in greater expression of cardiac proteins in vitro and improved ejection fraction (Numasawa et al). Another example of stem cell pre-treatment is provided by Duijvestein and colleagues who demonstrated γ-interferon treated MSCs improved their use in the treatment for colitis (Duijvestein et al).
Another promising approach is to partially differentiate the MSCs in culture and then remove the differentiating factors/conditions to cause partial de-differentiation before implanting in vivo. Chan and colleagues took this approach to first differentiate MSCs under neurogenic conditions in vitro, removed the differentiation conditions and implanted the cells in a neonatal rat model of ischemic brain injury. They noted improved engraftment, greater neuronal differentiation and elevated cognitive function (Liu/Chan). Notably, the bcl-2 family of proteins is involved, as is microRNA-34a. Such pre-educated MSCs or other stem cells may improve the immediate survival, tissue engraftment/ differentiation, and eventual therapeutic outcomes of stem cell treatments.

MSCs and Cancer
Mutations leading to hematopoietic malignancies gave much insight into the cell origins of HSCs but the same approach has not been as useful for identifying in vivo MSC precursors. In this regard, the review by Hogendorn (Hogendorn et al) on sarcomas –mesenchymal tumors – and the report from de Carvalho on gliosarcoma (de Carvalo et al) are important reading. MSCs are part of the stromal tissue that infiltrates many tumors. This leads to the obvious and important question of whether MSCs might be the origin of the tumor, or are they instead the support tissue providing growth factors and cytokines and increasing vascularity? Other reports present the opposite view that MSCs can reduce tumor growth. Klopp et al have reviewed this area and provide insight into the yin-yang effects of MSCs on tumorigenesis (Klopp et al). MSCs migrate to sites of cancer- “wounds that do not heal”- and this attribute has been effectively utilized to detect and image tumors (Kaplan et al) and MSCs expressing the tumor necrosis factor related apoptosis inducing ligand (aka TRAIL) elicited by tumor necrosis factor have been reported to inhibit pancreatic carcinoma cells (Mohr et al), and in conjunction with irradiation to increase the homing (tumor tropism) of MSCs to glioma (Jeun et al). A review by Tolar and colleagues points out the many challenges of producing a therapeutic MSC population for treatment in hematopoietic malignancies (Tolar et al).

Further defining MSCs
The early definition for MSCs required a homogeneous population (that is, not a collection of separate stem or progenitor cells) that could be propagated and would differentiate to multiple mesenchymal lineages. The use of antibodies to MSC surface markers provided convenient characterization and insight into cellular interactions. Flow cytometry made it easy to see if multiple cell populations were present in the cultured cells. Therefore, most MSC clinical trials utilize the first generation MSCs, with little change in the therapeutic product from that described over a decade ago. However, many authors now refer to MSCs as heterogeneous without clarifying their meaning. Careful isolation and culture technique limits heterogeneity. However, microheterogeneity, either stochastic or culture induced is a property of stem cells.Even a single MSC grown to the colony stage can demonstrate a range of phenotypes and differentiation responses from the stationary, crowded cell at the colony center to the actively mobile cells at the periphery. With that in mind, it is good to see publications that use newer tools to further characterize MSCs and that may lend themselves to better propagation, quality control and improved clinical outcomes. Russell et al carefully analyzed clones of MSCs to refine the standard three lineage differentiation assay and to develop greater insight (Russell et al). Analysis of the MSC transcriptome was mentioned earlier. Chen and co-workers identified miRNA204/211 as a regulator of runx2 and the osteogenic differentiation of MSCs (Chen et al). Relatedly, miR-17 is part of a positive osteogenic differentiation pathway in MSCs (Jin et al). We should hope to see more refinement and more useful stratification of MSCs in the future.

Relationship of MSCs to other stem cells
Perhaps no area of biology is potentially more confusing than the relationship of one type of stem/progenitor cell to another stem/progenitor cell. The relationship of MSCs to other types of stem cells is complex and is unraveling slowly. As MSCs and hematopoietic stem cells share a mesenchymal origin there should be a common predecessor but it has proven elusive to date, and the possibility of de-differentiating an MSC or HSC to the stage that allows interconversion has not been successfully accomplished. Even within the folds of MSCs we have a variety of names from different labs that are producing similar but perhaps not identical cells. Can these different cells be converted one to the other by changing the culture conditions or tweaking particular transcription factors? A partial answer is provided by Roobrouck et al who found that th different cell types MSC, multipotential adult progenitor cell (MAPC) and muscle mesangioblasts (Mab) became much more similar when cultured under the same conditions (Roobrouck et al). They also provided further characterization of the transcriptome of the cells, an approach that is not yet common but should be. Along these lines, Lai et al examined the role of fibroblast growth factor 2 (FGF-2 or basic FGF), commonly found in serum, in inducing expression of Twist2 and Spry4, transcription factors important in keeping MSCs in the undifferentiated state (Lai et al).

Lastly, if your Kindle just can’t hold all of this, a broad concise review by Salem and Thiemermann will provide ample overview of the current state of MSC science and therapeutics (Salem and Thiemmermann, 2010).

MicroRNA-204 Regulates Runx2 Protein Expression and Mesenchymal Progenitor Cell Differentiation
Jian Huang, Lan Zhao, Lianping Xing, Di Chen

Mesenchymal Stromal Cells - Current Understanding and Clinical Status
Husein K. Salem, Chris Thiemermann

In Vitro High-Capacity Assay to Quantify the Clonal Heterogeneity in Trilineage Potential of Mesenchymal Stem Cells Reveals a Complex
Hierarchy of Lineage Commitment

Katie C. Russell, Donald G. Phinney, Michelle R. Lacey, Bonnie L. Barrilleaux, Kristin E. Meyertholen, Kim C. O'Connor

A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke
Jin Soo Lee, Ji Man Hong, Gyeong Joon Moon, Phil Hyu Lee, Young Hwan Ahn, Oh Young Bang

Hitting the right spot with mesenchymal stromal cells (MSCs)
Jakub Tolar, Katarina Le Blanc, Armand Keating, Bruce R. Blazar

Mesenchymal Stem Cell Treatment of Complications of Diabetes Mellitus
Vladislav Volarevic, Nebojsa Arsenijevic, Miodrag L. Lukic, Miodrag Stojkovic

Dissecting a Discrepancy in the Literature: Do Mesenchymal Stem Cells Support or Suppress Tumor Growth?
Ann H. Klopp, Anshul Gupta, Erika Spaeth, Michael Andreeff, Frank Marini III

Mesenchymal-Lineage Stem Cells Have Pronounced Anti-Inflammatory Effects in the Twitcher Mouse Model of Krabbe's Disease
Cynthia B. Ripoll, Mette Flaat, Jessica Klopf-Eiermann, Jeanne M. Fisher-Perkins, Cynthia B. Trygg, Brittni A. Scruggs,
Marjorie L. McCants, Helen Paige Leonard, Amy F. Lin, Shijia Zhang, Michelle E. Eagle, Xavier Alvarez, Yu Teh Li, Su Chen Li, Jeffrey M. Gimble, Bruce A. Bunnell

Mesenchymal Tumors: When Stem Cells Go Mad
Alexander B. Mohseny, Pancras C. W. Hogendoorn

Concise Review: Mesenchymal Stem Cells for Acute Lung Injury: Role of Paracrine Soluble Factors
Jae W. Lee, Xiaohui Fang, Anna Krasnodembskaya, James P. Howard, Michael A. Matthay

Key Papers from Japan in Stem Cells

The STEM CELLS Editors are pleased to produce this Virtual Issue that reprints key peer-accepted publications devoted to stem cells from Japanese authors.

Significance of Remyelination by Neural Stem/Progenitor Cells Transplanted into the Injured Spinal Cord
Akimasa Yasuda

Human Cardiac Progenitor Cell Grafts as Unrestricted Source of Supernumerary Cardiac Cells in Healty Murine Hearts
Giancarlo Forte

From Hair to Cornea: Toward the Therapeutic Use of Hair Follicle-Derived Stem Cells in the Treatment of Limba Stem Cell Deficiency
Ewa Anna Meyer-Blazejewska

FEpithelial-Connective Tissue interactions Induced by Thyroid Hormone Receptor are Essential for Adult Stem Cell Development in the Xenopus laevis Intestine
Takashi Hasebe

Pretreatment of Human Mesenchymal Stem Cells with Pioglitazone Improved Efficiency of Cardiomyogenic Transdifferentiation and Cardiac Function
Daisuke Shinmura

Production of Mouse Embryonic Stem Cell Lines from Maturing Oocytes by Direct Conversion of Meiosis into Mitosis
Helena Fulka

Combination of a Ptgs Inhibitor and an Epidermal Growth Factor Receptor-Signaling Inhibitor Prevents Tumorigenesis of Oligodendrocyte Lineage-Derived Glioma Initiating Cells
Takuichiro Hide

LacdiNAc (GalNAcβ1-4GleNAc) Contributes to Self-Renewal of Mouse Embryonic Stem Cells by Regulating Leukemia Inhibitory Factor/STAT3 Signaling
Norihiko Sasaki

CC Chemokine Ligand 2 and Leukemia Inhibitory Factor Cooperatively Promote Pluripotency in Mouse Induced Pluripotent Cells
Yuki Hasegawa

Fox O3a Functions as a Key Integrator of Cellular Signals That Control Glioblastoma Stem-like Cell Differentiation and Tumorigenicity
Jun Sunayama

Radical Acceleration of Nuclear Reprogramming by Chromatin Remodeling with the Transactivation Domain of MyoD
Hiroyuki Harai

Crucial Role of C-Myc in the Generation of Induced Pluripotent Stem Cells
Ryoko Araki

Treatment of Human Mesenchymal Stem Cells with Angioensin Receptor Blocker Improved Efficiency of Cardiomyogenic Transdifferentiation and Improved Cardiac Function via Angiogenesis
Yohei Numasawa

CD133 Cancer Stem Cell-like Cells Derived from Uterine Carcinosarcoma (Malignant Mixed Mullerian Tumors)
Batsuren Choijamts

Circulating Endothelial Progenitor Cells for Vascular Medicine
Takayuki Asahara

Low Level of C-Kit Expression Marks Deeply Quiescent Murine Hematopoietic Stem Cells
Yoshikazu Matsuoka

Core Binding Factor Beta Functions in the Maintenance of Stem Cells and Orchestrates Continuous Proliferation and Differentiation in Mouse Incisors
Hiroshi Kurosaka

Gene Expression Profiling of Neural Stem Cells and Identification Regulators of Neural Differentiation During Cortical Development
Toshiyuki Ohtsuka

MEK-ERK Signaling Dictates DNA-Repair Gene MGMT Expression and Temozolomide Resistance of Stem-Like Glioblastoma Cells via the MDM2-p53 Axis
Atsushi Sato

Key Papers in Stem Cells and Regenerative Medicine

The STEM CELLS Editors are pleased to produce this Virtual Issue that reprints key peer-accepted publications devoted to stem cells and regenerative medicine.

Reprogramming of Postnatal Neurons into Induced Pluripotent Stem Cells by Defined Factors
Jong-Pil Kim, Rudolf Jaenisch

Lineage Specific Methylation of the Elf5 Promoter in Mammary Epithelial Cells
Heather Lee, Jane E. Visvader

Single Transcription Factor Reprogramming of Hair Follicle Dermal Papilla Cells to Induced Pluripotent Stem Cells
Su-Yi Tsai, Ihor R. Lemischka

Human Placenta-Derived Adherent Cells Prevent Bone loss, Stimulate Bone formation, and Suppress Growth of Multiple Myeloma in Bone
Xin Li, Robert Hariri

The Adult Mouse Dentate Gyrus Contains Populations of Committed Progenitor Cells that are Distinct from Subependymal Zone Neural Stem Cells
Laura Clarke, Derek van der Kooy

Concise Review: Pluripotency and the Transcriptional Inactivation of the Female Mammalian X Chromosome
Alissa Minkovsky, Sanjeet Patel, Kathrin Plath

Genome-Wide Studies Reveal That Lin28 Enhances the Translation of Genes Important for Growth and Survival of Human Embryonic Stem Cells
Shuping Peng, Haifan Lin

Molecular and Functional Characterizations of Gastrula Organizer Cells Derived from Human Embryonic Stem Cells
Nadav Sharon, Nissim Benvenisty

Aldehyde Dehydrogenase Activity Is a Biomarker of Primitive Normal Human Mammary Luminal Cells
Peter Eirew, Connie J. Eaves

TAp63 Is Important for Cardiac Differentiation of Embryonic Stem Cells and Heart Development
Matthieu Rouleau, Daniel Aberdam

Oxygen Levels Epigenetically Regulate Fate Switching of Neural Precursor Cells via Hypoxia-Inducible Factor 1α-Notch Signal Interaction in the Developing Brain
Tetsuji Mutoh, Kinichi Nakashima

Xenotransplanted Embryonic Kidney Provides A Niche for Endogenous Mesenchymal Stem Cell Differentiation into Erythropoietin-Producing Tissue
Kei Matsumoto, Takashi Yokoo

Best Papers From Our 2011 Young Investigators

The STEM CELLS Young Investigator Award honors a young scientist who is principal author of a significant research paper published in STEM CELLS. The 2011 prize is co-sponsored by the City and University of Kragujevac, with the winner presenting at the 2011 Symposium. The STEM CELLS Editors support the efforts of these emerging researchers and encourage the development of these young investigators who are making significant impacts in this field.

Adult Stem Cells Exhibit Global Suppression of RNA Polymerase II Serine-2 Phosphorylation
Rasmus Freter, Masatake Osawa, Shin-Ichi Nishikawa

Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells
Nessy John, Paolo Cinelli, Michael Wegner, Lukas Sommer

From Hair to Cornea: Toward the Therapeutic Use of Hair Follicle-Derived Stem Cells in the Treatment of Limbal Stem Cell Deficiency
Ewa Anna Meyer-Blazejewska, Mindy K. Call, Osamu Yamanaka, Hongshan Liu, Ursula Schlötzer-Schrehardt, Friedrich E. Kruse, Winston W. Kao

Transplanted Oligodendrocytes and Motoneuron Progenitors Generated from Human Embryonic Stem Cells Promote Locomotor Recovery After Spinal Cord Transection
Slaven Erceg, Mohammad Ronaghi, Marc Oria, Mireia García Roselló, Maria Amparo Pérez Aragó, Maria Gomez Lopez, Ivana Radojevic, Victoria Moreno-Manzano, Francisco-Javier Rodríguez-Jiménez, Shom Shanker Bhattacharya, Juan Cordoba, Miodrag Stojkovic

Reprogramming of Trophoblast Stem Cells into Pluripotent Stem Cells by Oct4
Tong Wu, Haitao Wang, Jing He, Lan Kang, Yonghua Jiang, Jinchao Liu, Yu Zhang, Zhaohui Kou, Lijun Liu, Xuehong Zhang, Shaorong Gao

Human Induced Pluripotent Stem Cell Lines Show Stress Defense Mechanisms and Mitochondrial Regulation Similar to Those of Human Embryonic Stem Cells
Lyle Armstrong, Katarzyna Tilgner, Gabriele Saretzki, Stuart P. Atkinson, Miodrag Stojkovic, Ruben Moreno, Stefan Przyborski, Majlinda Lako

Bone Marrow Mononuclear Cells Promote Proliferation of Endogenous Neural Stem Cells Through Vascular Niches After Cerebral Infarction
Akiko Nakano-Doi, Takayuki Nakagomi, Masatoshi Fujikawa, Nami Nakagomi, Shuji Kubo, Shan Lu, Hiroo Yoshikawa, Toshihiro Soma, Akihiko Taguchi, Tomohiro Matsuyama

A Fibrin Patch-Based Enhanced Delivery of Human Embryonic Stem Cell-Derived Vascular Cell Transplantation in a Porcine Model of Postinfarction Left Ventricular Remodeling
Qiang Xiong, Katherine L. Hill, Qinglu Li, Piradeep Suntharalingam, Abdul Mansoor, Xiaohong Wang, Mohammad Nurulqadr Jameel, Pengyuan Zhang, Cory Swingen, Dan S. Kaufman, Jianyi Zhang

Antibacterial Effect of Human Mesenchymal Stem Cells Is Mediated in Part from Secretion of the Antimicrobial Peptide LL-37
Anna Krasnodembskaya, Yuanlin Song, Xiaohui Fang, Naveen Gupta, Vladimir Serikov, Jae-Woo Lee, Michael A. Matthay

Inhibition of Ataxia Telangiectasia- and Rad3 -Related Function Abrogates the In Vitro and In Vivo Tumorigenicity of Human Colon Cancer Cells Through Depletion of the CD133 Tumor-Initiating Cell Fraction
Eike Gallmeier, Patrick C. Hermann, Maria-Theresa Mueller, Juan G. Machado, Andreas Ziesch, Enrico N. De Toni, Andreas Palagyi, Christian Eisen, Joachim W. Ellwart, Jose Rivera, Belen Rubio-Viqueira, Manuel Hidalgo, Fred Bunz, Burkhard Göke, Christopher Heeschen

Editor's Choice: The best of our Induced Pluripotent Stem Cells papers

In this virtual issue, the editor is pleased to present his pick of the best of the iPSC (induced pluripotent stem cells) papers in the last two years. Below are the top ten of his selections.

Induced Pluripotent Stem Cell Generation Using a Single Lentiviral Stem Cell Cassette
Cesar A. Sommer, Matthias Stadtfeld, George J. Murphy, Konrad Hochedlinger, Darrell N. Kotton, Gustavo Mostoslavsky

Directed Differentiation of Human-Induced Pluripotent Stem Cells Generates Active Motor Neurons
Saravanan Karumbayaram, Bennett G. Novitch, Michaela Patterson, Joy A. Umbach, Laura Richter, Anne Lindgren, Anne E. Conway, Amander T. Clark, Steve A. Goldman, Kathrin Plath, Martina Wiedau-Pazos, Harley I. Kornblum, William E. Lowry

Hemangioblastic Derivatives from Human Induced Pluripotent Stem Cells Exhibit Limited Expansion and Early Senescence
Qiang Feng, Shi-Jiang Lu, Irina Klimanskaya, Ignatius Gomes, Dohoon Kim, Young Chung, George R. Honig, Kwang-Soo Kim, Robert Lanza

Polycistronic Lentiviral Vector for Hit and Run Reprogramming of Adult Skin Fibroblasts to Induced Pluripotent Stem Cells
Chia-Wei Chang, Yi-Shin Lai, Kevin M. Pawlik, Kaimao Liu, Chiao-Wang Sun, Chao Li, Trenton R. Schoeb, Tim M. Townes

Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells
Wenbo Zhou, Curt R. Freed

Clone- and Gene-Specific Aberrations of Parental Imprinting in Human Induced Pluripotent Stem Cells
Marjorie Pick, Yonatan Stelzer, Ori Bar-Nur, Yoav Mayshar, Amir Eden, Nissim Benvenisty

Derivation of Functional Retinal Pigmented Epithelium from Induced Pluripotent Stem Cells
David E. Buchholz, Sherry T. Hikita, Teisha J. Rowland, Amy M. Friedrich, Cassidy R. Hinman, Lincoln V. Johnson, Dennis O. Clegg

Generation of Human-Induced Pluripotent Stem Cells in the Absence Exogenous Sox2
Wenlin Li, Hongyan Zhou, Ramsey Abujarour, Saiyong Zhu, Jin Young Joo, Tongxiang Lin, Ergeng Hao, Hans R. Schoeler, Alberto Hayek, Sheng Ding

Excision of Reprogramming Transgenes Improves the Differentiation Potential of iPS Cells Generated with a Single Excisable Vector
Cesar A. Sommer, Andreia Gianotti Sommer, Tyler A. Longmire, Constantina Christodoulou, Dolly D. Thomas, Monica Gostissa, Fred W. Alt, George J. Murphy, Darrell N. Kotton, Gustavo Mostoslavsky

Butyrate Greatly Enhances Derivation of Human Induced Pluripotent Stem Cells by Promoting Epigenetic Remodeling and the Expression of Pluripotency-Associated Genes
Prashant Mali, Bin-Kuan Chou, Jonathan Yen, Zhaohui Ye, Jizhong Zou, Sarah Dowey, Robert A. Brodsky, Joyce E. Ohm, Wayne Yu, Stephen B. Baylin, Kosuke Yusa, Allan Bradley, David J. Meyers, Chandrani Mukherjee, Philip A. Cole, Linzhao Cheng

Best Papers From Our 2010 Young Investigators

The STEM CELLS Young Investigator Award honors a young scientist who is principal author of a significant research paper published in STEM CELLS. This prize is currently co-sponsored by the International Stem Cells Symposium, with the winner presenting at the 2010 Symposium. The STEM CELLS Editors support the efforts of these emerging researches and encourage the development of these young investigators who are making significant impacts in this field. Below are the distinguished finalists for the 2010 award.

Tissue-Specific Stem Cells
Regenerative Effects of Transplanted Mesenchymal Stem Cells in Fracture Healing
Froilán Granero-Moltó

Tissue-Specific Stem Cells
Intracerebral Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells Reduces Amyloid-Beta Deposition and Rescues Memory Deficits in Alzheimer's Disease Mice by Modulation of Immune Responses
Hee Kyung Jin

Tissue-Specific Stem Cells
Mesenchymal Stem Cells Promote Matrix Metalloproteinase Secretion by Cardiac Fibroblasts and Reduce Cardiac Ventricular Fibrosis After Myocardial Infarction Céline Mias

The Stem Cell Niche
Endothelial Cells Support Survival, Proliferation, and Neuronal Differentiation of Transplanted Adult Ischemia-Induced Neural Stem/Progenitor Cells After Cerebral Infarction
Takayuki Nakagomi

Embryronic Stem Cells/Induced Pluripotent Stem Cells
Oct4 and Klf4 Reprogram Dermal Papilla Cells into Induced Pluripotent Stem Cells
Michael Rendl

Tissue-Specific Stem Cells
Life-Sparing Effect of Human Cord Blood-Mesenchymal Stem Cells in Experimental Acute Kidney Injury
Cinzia Rota

Embryronic Stem Cells/Induced Pluripotent Stem Cells
Signaling Pathways Controlling Pluripotency and Early Cell Fate Decisions of Human Induced Pluripotent Stem Cells
Ludovic Vallier

Translational and Clinical Research

Concise Review: Adipose Tissue-Derived Stromal Cells - Basic and Clinical Implications for Novel Cell-Based Therapies
Andreas Schäffler, Christa Büchler

Concise Review: Mesenchymal Stem/Multipotent Stromal Cells: The State of Transdifferentiation and Modes of Tissue Repair - Current Views
Donald G. Phinney, Darwin J. Prockop

Human Leukocyte Antigen-G5 Secretion by Human Mesenchymal Stem Cells Is Required to Suppress T Lymphocyte and Natural Killer Function and to Induce CD4 CD25highFOXP3 Regulatory T Cells
Zohair Selmani, Abderrahim Naji, Ines Zidi, Benoit Favier, Emilie Gaiffe, Laurent Obert, Christophe Borg, Philippe Saas, Pierre Tiberghien, Nathalie Rouas-Freiss, Edgardo D. Carosella, Frederic Deschaseaux

Persistent Dopamine Functions of Neurons Derived from Embryonic Stem Cells in a Rodent Model of Parkinson Disease
Jose A. Rodríguez-Gómez, Jian-Qiang Lu, Iván Velasco, Seth Rivera, Sami S. Zoghbi, Jeih-San Liow, John L. Musachio, Frederick T. Chin, Hiroshi Toyama, Jurgen Seidel, Michael V. Green, Panayotis K. Thanos, Masanori Ichise, Victor W. Pike, Robert B. Innis, Ron D. G. McKay

Mesenchymal Stem Cells Inhibit the Differentiation of Dendritic Cells Through an Interleukin-6-Dependent Mechanism
Farida Djouad, Louis-Marie Charbonnier, Carine Bouffi, Pascale Louis-Plence, Claire Bony, Florence Apparailly, Céline Cantos, Christian Jorgensen, Danièle Noël

Human AB Serum and Thrombin-Activated Platelet-Rich Plasma Are Suitable Alternatives to Fetal Calf Serum for the Expansion of Mesenchymal Stem Cells from Adipose Tissue
Asli Kocaoemer, Susanne Kern, Harald Klüter, Karen Bieback

Cells Isolated from Umbilical Cord Tissue Rescue Photoreceptors and Visual Functions in a Rodent Model of Retinal Disease
Raymond D. Lund, Shaomei Wang, Bin Lu, Sergej Girman, Toby Holmes, Yves Sauvé, Darin J. Messina, Ian R. Harris, Anthony J. Kihm, Alexander M. Harmon, Feng-Yi Chin, Anna Gosiewska, Sanjay K. Mistry

Concise Review: No Breakthroughs for Human Mesenchymal and Embryonic Stem Cell Culture: Conditioned Medium, Feeder Layer, or Feeder-Free; Medium with Fetal Calf Serum, Human Serum, or Enriched Plasma; Serum-Free, Serum Replacement Nonconditioned Medium, or Ad Hoc Formula? All That Glitters Is Not Gold!
Ferdinando Mannello, Gaetana A. Tonti

MicroRNA-134 Modulates the Differentiation of Mouse Embryonic Stem Cells, Where It Causes Post-Transcriptional Attenuation of Nanog and LRH1
Yvonne M.-S. Tay, Wai-Leong Tam, Yen-Sin Ang, Philip M. Gaughwin, Henry Yang, Weijia Wang, Rubing Liu, Joshy George, Huck-Hui Ng, Ranjan J. Perera, Thomas Lufkin, Isidore Rigoutsos, Andrew M. Thomson, Bing Lim

Concise Review: Therapeutic Strategies for Parkinson Disease Based on the Modulation of Adult Neurogenesis
Martine Geraerts, Olga Krylyshkina, Zeger Debyser, Veerle Baekelandt

Concise Review: Isolation and Characterization of Cells from Human Term Placenta: Outcome of the First International Workshop on Placenta Derived Stem Cells
Ornella Parolini, Francesco Alviano, Gian Paolo Bagnara, Grozdana Bilic, Hans-Jörg Bühring, Marco Evangelista, Simone Hennerbichler, Bing Liu, Marta Magatti, Ning Mao, Toshio Miki, Fabio Marongiu, Hideaki Nakajima, Toshio Nikaido, C. Bettina Portmann-Lanz, Venkatachalam Sankar, Maddalena Soncini, Guido Stadler, Daniel Surbek, Tsuneo A. Takahashi, Heinz Redl, Norio Sakuragawa, Susanne Wolbank, Steffen Zeisberger, Andreas Zisch, Stephen C. Strom

Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors
Robert W. Cho, Xinhao Wang, Maximilian Diehn, Kerby Shedden, Grace Y. Chen, Gavin Sherlock, Austin Gurney, John Lewicki, Michael F. Clarke

Spheres Isolated from 9L Gliosarcoma Rat Cell Line Possess Chemoresistant and Aggressive Cancer Stem-Like Cells
Ali Jourabchi Ghods, Dwain Irvin, Gentao Liu, Xiangpeng Yuan, Iman R. Abdulkadir, Patrizia Tunici, Bindu Konda, Sebastian Wachsmann-Hogiu, Keith L. Black, John S. Yu

N-Glycolylneuraminic Acid Xenoantigen Contamination of Human Embryonic and Mesenchymal Stem Cells Is Substantially Reversible
Annamari Heiskanen, Tero Satomaa, Sari Tiitinen, Anita Laitinen, Sirkka Mannelin, Ulla Impola, Milla Mikkola, Cia Olsson, Halina Miller-Podraza, Maria Blomqvist, Anne Olonen, Hanna Salo, Petri Lehenkari, Timo Tuuri, Timo Otonkoski, Jari Natunen, Juhani Saarinen, Jarmo Laine

Multipotent Stem Cells from Umbilical Cord: Cord Is Richer than Blood!
Mariane Secco, Eder Zucconi, Natassia M. Vieira, Luciana L.Q. Fogaça, Antonia Cerqueira, Maria Denise F. Carvalho, Tatiana Jazedje, Oswaldo K. Okamoto, Alysson R. Muotri, Mayana Zatz

Concise Review: Prospects of Stem Cell Therapy for Temporal Lobe Epilepsy
shok K. Shetty, Bharathi Hattiangady

Complete Spinal Cord Injury Treatment Using Autologous Bone Marrow Cell Transplantation and Bone Marrow Stimulation with Granulocyte Macrophage-Colony Stimulating Factor: Phase I/II Clinical Trial
Seung Hwan Yoon, Yu Shik Shim, Yong Hoon Park, Jong Kwon Chung, Jung Hyun Nam, Myung Ok Kim, Hyung Chun Park, So Ra Park, Byoung-Hyun Min, Eun Young Kim, Byung Hyune Choi, Hyeonseon Park, Yoon Ha

Xenotransplantation of Long-Term-Cultured Swine Bone Marrow-Derived Mesenchymal Stem Cells
Yasuhiro Nakamura, Xiaohong Wang, Chengsu Xu, Atsushi Asakura, Minoru Yoshiyama, Arthur H.L. From, Jianyi Zhang

Molecular Profiling of CD34 Cells in Idiopathic Myelofibrosis Identifies a Set of Disease-Associated Genes and Reveals the Clinical Significance of Wilms' Tumor Gene 1 (WT1)
Paola Guglielmelli, Roberta Zini, Costanza Bogani, Simona Salati, Alessandro Pancrazzi, Elisa Bianchi, Francesco Mannelli, Sergio Ferrari, Marie-Caroline Le Bousse-Kerdilès, Alberto Bosi, Giovanni Barosi, Anna Rita Migliaccio, Rossella Manfredini, Alessandro M. Vannucchi

Toll-Like Receptors on Human Mesenchymal Stem Cells Drive Their Migration and Immunomodulating Responses
Suzanne L. Tomchuck, Kevin J. Zwezdaryk, Seth B. Coffelt, Ruth S. Waterman, Elizabeth S. Danka, Aline B. Scandurro


Cancer Stem Cells

Sarcoma Derived from Cultured Mesenchymal Stem Cells
Jakub Tolar, Alma J. Nauta, Mark J. Osborn, Angela Panoskaltsis Mortari, Ron T. McElmurry, Scott Bell, Lily Xia, Ning Zhou, Megan Riddle, Tania M. Schroeder, Jennifer J. Westendorf, R. Scott McIvor, Pancras C.W. Hogendoorn, Karoly Szuhai, LeAnn Oseth, Betsy Hirsch, Stephen R. Yant, Mark A. Kay, Alexandra Peister, Darwin J. Prockop, Willem E. Fibbe, Bruce R. Blazar

Cyclopamine-Mediated Hedgehog Pathway Inhibition Depletes Stem-Like Cancer Cells in Glioblastoma
Eli E. Bar, Aneeka Chaudhry, Alex Lin, Xing Fan, Karisa Schreck, William Matsui, Sara Piccirillo, Angelo L. Vescovi, Francesco DiMeco, Alessandro Olivi, Charles G. Eberhart

Concise Review: Multipotent Mesenchymal Stromal Cells in Blood
Qiling He, Chao Wan, Gang Li

Differential Gene Expression Associated with Migration of Mesenchymal Stem Cells to Conditioned Medium from Tumor Cells or Bone Marrow Cells
Lata G. Menon, Sonia Picinich, Rajeth Koneru, Hui Gao, Siang Yo Lin, Mythili Koneru, Philipp Mayer-Kuckuk, John Glod, Debabrata Banerjee

Spontaneous Transformation of Human Adult Nontumorigenic Stem Cells to Cancer Stem Cells Is Driven by Genomic Instability in a Human Model of Glioblastoma
Anjali Shiras, Sivarajan T Chettiar, Varsha Shepal, Ganeshkumar Rajendran, G. Rajendra Prasad, Padma Shastry

Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors
obert W. Cho, Xinhao Wang, Maximilian Diehn, Kerby Shedden, Grace Y. Chen, Gavin Sherlock, Austin Gurney, John Lewicki, Michael F. Clarke

Spheres Isolated from 9L Gliosarcoma Rat Cell Line Possess Chemoresistant and Aggressive Cancer Stem-Like Cells
AAli Jourabchi Ghods, Dwain Irvin, Gentao Liu, Xiangpeng Yuan, Iman R. Abdulkadir, Patrizia Tunici, Bindu Konda, Sebastian Wachsmann-Hogiu, Keith L. Black, John S. Yu

Concise Review: Stem Cell Antigen-1: Expression, Function, and Enigma
Christina Holmes, William L. Stanford

Identification of a Novel Putative Gastrointestinal Stem Cell and Adenoma Stem Cell Marker, Doublecortin and CaM Kinase-Like-1, Following Radiation Injury and in Adenomatous Polyposis Coli/Multiple Intestinal Neoplasia Mice
Randal May, Terrence E. Riehl, Clayton Hunt, Sripathi M. Sureban, Shrikant Anant, Courtney W. Houchen

Concise Review: Roles of Polycomb Group Proteins in Development and Disease: A Stem Cell Perspective
Vinagolu K. Rajasekhar, Martin Begemann

p66Shc/Notch-3 Interplay Controls Self-Renewal and Hypoxia Survival in Human Stem/Progenitor Cells of the Mammary Gland Expanded In Vitro as Mammospheres
Pasquale Sansone, Gianluca Storci, Catia Giovannini, Silvia Pandolfi, Simona Pianetti, Mario Taffurelli, Donatella Santini, Claudio Ceccarelli, Pasquale Chieco, Massimiliano Bonafé

Bmi-1-Green Fluorescent Protein-Knock-In Mice Reveal the Dynamic Regulation of Bmi-1 Expression in Normal and Leukemic Hematopoietic Cells
Naoki Hosen, Toshiyuki Yamane, Manja Muijtjens, Kara Pham, Michael F. Clarke, Irving L. Weissman

Bone Marrow Contributes to Epithelial Cancers in Mice and Humans as Developmental Mimicry
Christopher R. Cogle, Neil D. Theise, DongTao Fu, Deniz Ucar, Sean Lee, Steven M. Guthrie, Jean Lonergan, Witold Rybka, Diane S. Krause, Edward W. Scott

Donor-Derived Human Bone Marrow Cells Contribute to Solid Organ Cancers Developing After Bone Marrow Transplantation
Itzhak Avital, Andre L. Moreira, David S. Klimstra, Margaret Leversha, Esperanza B. Papadopoulos, Murray Brennan, Robert J. Downey

Concise Review: Wharton's Jelly-Derived Cells Are a Primitive Stromal Cell Population
Deryl L. Troyer, Mark L. Weiss

Absence of OCT4 Expression in Somatic Tumor Cell Lines
Tobias Cantz, Göran Key, Martina Bleidibetael, Luca Gentile, Dong Wook Han, Alexandra Brenne, Hans R. Schöler

Sonic Hedgehog Stimulates Mouse Embryonic Stem Cell Proliferation by Cooperation of Ca2 /Protein Kinase C and Epidermal Growth Factor Receptor As Well as Gli1 Activation
Jung Sun Heo, Min Young Lee, Ho Jae Han

Enhanced Unique Pattern of Hematopoietic Cell Mobilization Induced by the CXCR4 Antagonist 4F-Benzoyl-TN14003
Michal Abraham, Katia Biyder, Michal Begin, Hanna Wald, Ido D. Weiss, Eithan Galun, Arnon Nagler, Amnon Peled

Concise Review: Cancer/Testis Antigens, Stem Cells, and Cancer
Fabrício F. Costa, Katarina Le Blanc, Bertha Brodin

Concise Review: Adult Multipotent Stromal Cells and Cancer: Risk or Benefit?
Gwendal Lazennec, Christian Jorgensen


Key Papers From Asia in Stem Cells and Regenerative Medicine

Editors' Note:

The Editors are pleased to produce this Virtual Issue that reprints key peer-accepted publications devoted to stem cells and regenerative medicine. The issue covers many fields, including:

Neural Induction with Neurogenin1 Increases the Therapeutic Effects of Mesenchymal Stem Cells in the Ischemic Brain

Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease

Robo4 is expressed on hematopoietic stem cells and potentially involved in the niche-mediated regulation of the side population phenotype

CD105 positive cells in pulmonary arterial blood of adult human lung cancer patients include mesenchymal progenitors

Human Embryonic Stem Cell-Derived Mesenchymal Progenitors (EMPs) Possess Strong Immunosuppressive Effects Towards Natural Killer Cells as well as T Lymphocytes

IFATS Collection: Immunomodulatory Effects of Adipose Tissue-Derived Stem Cells in an Allergic Rhinitis Mouse Model
Kyu-Sup Cho, Hye-Kyung Park, Hee-Young Park, Jin Sup Jung, Seong-Gyu Jeon, Yoon-Keun Kim, Hwan Jung Roh

Thromboxane A2 Induces Differentiation of Human Mesenchymal Stem Cells to Smooth Muscle-Like Cells
Mi Ra Kim, Eun Su Jeon, Young Mi Kim, Jung Sub Lee, Jae Ho Kim

Notch Inhibition Promotes Human Embryonic Stem Cell-Derived Cardiac Mesoderm Differentiation
Jiho Jang, Seung Yup Ku, Jung Eun Kim, Kyunghee Choi, Yoon Young Kim, Hee Sun Kim, Sun Kyung Oh, Eun Ju Lee, Hyun-Jai Cho, Young Hwan Song, Sang Hun Lee, Suk Ho Lee, Chang Suk Suh, Seok Hyun Kim, Shin Yong Moon, Young Min Choi

Neural Induction with Neurogenin1 Increases the Therapeutic Effects of Mesenchymal Stem Cells in the Ischemic Brain
Sung-Soo Kim, Seung-Wan Yoo, Tae-Seok Park, Seung-Cheol Ahn, Han-Seong Jeong, Ji-Won Kim, Da-Young Chang, Kyung-Gi Cho, Seung U. Kim, Youngbuhm Huh, Jong-Eun Lee, Soo-Yeol Lee, Young-Don Lee, Haeyoung Suh-Kim

IFATS Collection: Selenium Induces Improvement of Stem Cell Behaviors in Human Adipose-Tissue Stromal Cells via SAPK/JNK and Stemness Acting Signals
Jeong Hwan Kim, Mi Ran Lee, Jee Hun Kim, Min Ki Jee, Soo Kyung Kang

TIS21/BTG2 Negatively Regulates Estradiol-Stimulated Expansion of Hematopoietic Stem Cells by Derepressing Akt Phosphorylation and Inhibiting mTOR Signal Transduction
Bong Cho Kim, Min Sook Ryu, S. Paul Oh, In Kyoung Lim

Osteopontin Promotes the Development of Natural Killer Cells from Hematopoietic Stem Cells
Jin Woong Chung, Mi Sun Kim, Zheng-Hao Piao, Mira Jeong, Suk Ran Yoon, Nara Shin, Sang Yong Kim, Eun Sook Hwang, Young Yang, Young Ho Lee, Young Sang Kim, Inpyo Choi

Pluripotin Combined with Leukemia Inhibitory Factor Greatly Promotes the Derivation of Embryonic Stem Cell Lines from Refractory Strains
Weifeng Yang, Wei Wei, Cheng Shi, Jinliang Zhu, Wenqin Ying, Yan Shen, Xin Ye, Lingling Fang, Shuguang Duo, Jie Che, Huan Shen, Sheng Ding, Hongkui Deng

Mesenchymal Stem Cells Alter Migratory Property of T and Dendritic Cells to Delay the Development of Murine Lethal Acute Graft-Versus-Host Disease
Hong Li, ZiKuan Guo, XiaoXia Jiang, Heng Zhu, XiuSen Li, Ning Mao

A Feeder-Free and Efficient Production of Functional Neutrophils from Human Embryonic Stem Cells
Koichi Saeki, Kumiko Saeki, Masako Nakahara, Satoko Matsuyama, Naoko Nakamura, Yoshiko Yogiashi, Asako Yoneda, Makoto Koyanagi, Yasushi Kondo, Akira Yuo

Roundabout 4 Is Expressed on Hematopoietic Stem Cells and Potentially Involved in the Niche-Mediated Regulation of the Side Population Phenotype
Fumi Shibata, Yuko Goto-Koshino, Yoshihiro Morikawa, Tadasuke Komori, Miyuki Ito, Yumi Fukuchi, Jeffrey P. Houchins, Monica Tsang, Dean Y. Li, Toshio Kitamura, Hideaki Nakajima

Quiescent Human Hematopoietic Stem Cells in the Bone Marrow Niches Organize the Hierarchical Structure of Hematopoiesis
Takashi Yahata, Yukari Muguruma, Shizu Yumino, Yin Sheng, Tomoko Uno, Hideyuki Matsuzawa, Mamoru Ito, Shunichi Kato, Tomomitsu Hotta, Kiyoshi Ando

IFATS Collection: Fibroblast Growth Factor-2-Induced Hepatocyte Growth Factor Secretion by Adipose-Derived Stromal Cells Inhibits Postinjury Fibrogenesis Through a c-Jun N-Terminal Kinase-Dependent Mechanism Stem Cells
Hirotaka Suga, Hitomi Eto, Tomokuni Shigeura, Keita Inoue, Noriyuki Aoi, Harunosuke Kato, Satoshi Nishimura, Ichiro Manabe, Koichi Gonda, Kotaro Yoshimura

Spatiotemporal Recapitulation of Central Nervous System Development by Murine Embryonic Stem Cell-Derived Neural Stem/Progenitor Cells
Yohei Okada, Arifumi Matsumoto, Takuya Shimazaki, Ryosuke Enoki, Amane Koizumi, Seiji Ishii, Yasuto Itoyama, Gen Sobue, Hideyuki Okano

Enrichment of Putative Pancreatic Progenitor Cells from Mice by Sorting for Prominin1 (CD133) and Platelet-Derived Growth Factor Receptor β
Yuichi Hori, Miki Fukumoto, Yoshikazu Kuroda

CD105-Positive Cells in Pulmonary Arterial Blood of Adult Human Lung Cancer Patients Include Mesenchymal Progenitors
Haruki Chiba, Genicihro Ishii, Ta-Kashi Ito, Kazuhiro Aoyagi, Hiroki Sasaki, Kanji Nagai, Atsushi Ochiai

Mood Stabilizing Drugs Expand the Neural Stem Cell Pool in the Adult Brain Through Activation of Notch Signaling
Mikito Higashi, Noriko Maruta, Alan Bernstein, Kazuhiro Ikenaka, Seiji Hitoshi

A Novel Isolation Technique of Progenitor Cells in Human Corneal Epithelium Using Non-Tissue Culture Dishes
Seiichi Yokoo, Satoru Yamagami, Takashi Shimada, Tomohiko Usui, Taka-aki Sato, Shiro Amano, Makoto Araie, Junji Hamuro

Spherically Symmetric Mesenchymal Stromal Cell Bodies Inherent with Endogenous Extracellular Matrices for Cellular Cardiomyoplasty
Chung-Chi Wang, Chun-Hung Chen, Shiaw-Min Hwang, Wei-Wen Lin, Chih-Hao Huang, Wen-Yu Lee, Yen Chang, Hsing-Wen Sung

Brief Report - Human Embryonic Stem Cell-Derived Mesenchymal Progenitors Possess Strong Immunosuppressive Effects Toward Natural Killer Cells as Well as T Lymphocytesty
B. Linju Yen, Chan Jung Chang, Ko-Jiunn Liu, Yao Chang Chen, Hsin-I Hu, Chi-Huey Bai, Men-Luh Yen