You have full text access to this Open Access content

EMBO Molecular Medicine

All articles accepted from 14 August 2012 are published under the terms of the Creative Commons Attribution License.   Articles accepted before this date were published under the agreement as stated in the final article.

Cover image for Vol. 7 Issue 5

Edited By: Stefanie Dimmeler (Chief Editor), Roberto Buccione and Céline Carret (EMBO Editors)

Online ISSN: 1757-4684

Virtual Issue: Stem Cells

For this virtual issue dedicated on Stem Cells, we have listed exciting new publications. In addition to giving you the opportunity to read about known experts in the field reflecting about their experiences and ideas on their favorite subject, we are continuously updating this special Stem Cells Virtual Issue with great new papers. Do not forget to check our Cancer Virtual Issue for more articles relating to Stem Cells research!

 


Role of stress-inducible protein-1 in recruitment of bone marrow derived cells into the ischemic brains
Shin-Da Lee, Ted Weita Lai, Shinn-Zong Lin, Chen-Huan Lin, Yung-Hsiang Hsu, Chi-Yuan Li, Hsiao-Jung Wang, Wei Lee, Ching-Yuan Su, Yung-Luen Yu and Woei-Cherng Shyu
EMBO Mol Med 2013, 5(8), 1227–1246

EMBO Molecular Medicine - Role of stress-inducible protein-1 in recruitment of bone marrow derived cells into the ischemic brains

This work identifies HIF-1a-mediated transcription of STI-1 and PrPc interaction as leading to BMDCs recruitment into ischemic brains following stroke in both patients and animal models of stroke, highlighting novel neuroprotective possibilities.


Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia
Gonçalo Regalo and Achim Leutz
EMBO Mol Med 2013, 5(8), 1154–1164

EMBO Molecular Medicine - Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia

This review discusses cell reprogramming, epithelial metaplasia and hematopoietic lineage ambiguity, and highlights changes in cell fate that occur during tumor initiation leading to discrepancies between tumors phenotype and their cellular origin.


Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain
Jose R. Pineda, Mathieu Daynac, Alexandra Chicheportiche, Arantxa Cebrian-Silla, Karine Sii Felice, Jose Manuel Garcia-Verdugo, François D. Boussin and Marc-André Mouthon
EMBO Mol Med 2013, 5(4), 548–562

EMBO Molecular Medicine - Vascular-derived TGF-ß increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain

In aged or irradiated mice, the neural stem cell vascular niche expresses increased levels of TGFbeta1, which induces apoptosis of neural stem cells via Smad3. Treatment with TGFbeta signaling blockers restores neurogenesis in these mice.


Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke
Yung-Luen Yu, Ruey-Hwang Chou, Woei-Cherng Shyu, Shu-Ching Hsieh, Chen-Shiou Wu, Shu-Ya Chiang, Wei-Jung Chang, Jia-Ni Chen, Yen-Ju Tseng, Yu-Hsuan Lin, Wei Lee, Su-Peng Yeh, Jennifer L. Hsu, Cheng-Chieh Yang, Shih-Chieh Hung and Mien-Chie Hung
EMBO Mol Med 2013, 5(4), 531–547

EMBO Molecular Medicine - Smurf2-mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke

Smurf2-mediated degradation of EZH2 enhances neuronal differentiation of human mesenchymal stem cells (hMSCs). This enables expression of PPARgamma in hMSCs, which when implanted improve recovery in a rat model of stroke.


Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart
Konstantinos Malliaras, Yiqiang Zhang, Jeffrey Seinfeld, Giselle Galang, Eleni Tseliou, Ke Cheng, Baiming Sun, Mohammad Aminzadeh and Eduardo Marbán
EMBO Mol Med 2013, 5(2), 191–209

EMBO Molecular Medicine - Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart

Cell therapy with cardiosphere-derived cells regenerates the infarcted adult mouse heart by increasing adult cardiomyocyte proliferation and recruiting endogenous stem cells.

Accompanying Closeup
Heart to heart: grafting cardiosphere-derived cells augments cardiac self-repair by both myocytes and stem cells
Jose A. Palacios and Michael D. Schneider
EMBO Mol Med 2013, 5(2), 177–179


The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets
Naomi Pode-Shakked, Rachel Shukrun, Michal Mark-Danieli, Peter Tsvetkov, Sarit Bahar, Sara Pri-Chen, Ronald S. Goldstein, Eithan Rom-Gross, Yoram Mor, Edward Fridman, Karen Meir, Amos Simon, Marcus Magister, Naftali Kaminski, Victor S. Goldmacher, Orit Harari-Steinberg and Benjamin Dekel
EMBO Mol Med 2013, 5(1), 18–37

EMBO Molecular Medicine - The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets

Here, the authors report the isolation and characterisation of Wilms' tumour stem cells and show that targeting a cancer cell population enriched for cancer-initiating cell activity leads to tumour eradication in a mouse model.

Accompanying Closeup
The stem and roots of Wilms' tumours
Peter Hohenstein
EMBO Mol Med 2013, 5(1), 4–6


Strategy for the creation of clinical grade hESC line banks that HLA-match a target population
Laureen Jacquet, Emma Stephenson, Robert Collins, Heema Patel, Jane Trussler, Roaa Al-Bedaery, Pamela Renwick, Caroline Ogilvie, Robert Vaughan and Dusko Ilic
EMBO Mol Med 2013, 5(1), 10–17

EMBO Molecular Medicine - Strategy for the creation of clinical grade hESC line banks that HLA-match a target population

The authors developed a preselection method for the generation of HLA-matched hESC line banks and show that whole genome amplification of genomic DNA from a single blastomere is sufficient for rapid, reliable and accurate SNP typing.


Krueppel-like factor 15 regulates Wnt/β-catenin transcription and controls cardiac progenitor cell fate in the postnatal heart
Zafiriou, Hans-Joerg Schaeffer, Anke Renger, Elena Pavlova, Rainer Dietz, Wolfram H. Zimmermann, Martin W. Bergmann and Laura C. Zelarayán
EMBO Mol Med 2012, 4(9), 992–1007

EMBO Molecular Medicine - Krueppel-like factor 15 regulates Wnt/ß-catenin transcription and controls cardiac progenitor cell fate in the postnatal heart

Wnt/beta-catenin pathway is essential for embryonic cardiogenesis and for normal cardiac homeostasis and remodeling. Here, the authors show a novel interaction between KLF15 and betacatenin/TCF4, which leads to repression of the Wnt transcriptional activity and regulates the cardiac progenitor cell fate in vivo.


Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF
Ji-Young Lee, Jimin Yang, Eun Ju Lee, Su-Yeon Kim, Seock-Won Youn, Jaewon Lee, Woo Jean Kim, Kyu-Won Kim, Jeong Mook Lim, Jong-Wan Park, Young-Bae Park and Hyo-Soo Kim
EMBO Mol Med 2012, 4(9), 924–938

EMBO Molecular Medicine - Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF

Hypoxia is shown here to efficiently direct mouse ESCs to differentiate into the vascular-lineage. Indeed, hypoxic priming decreases pluripotency through HIF-1-mediated Oct4 silencing and increases HIF-1-induced VEGF expression.


Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
Adriana Sánchez-Danés, Yvonne Richaud-Patin, Iria Carballo-Carbajal, Senda Jiménez-Delgado, Carles Caig, Sergio Mora, Claudia Di Guglielmo, Mario Ezquerra, Bindiben Patel, Albert Giralt, Josep M. Canals, Maurizio Memo, Jordi Alberch, José López-Barneo, Miquel Vila, Ana Maria Cuervo, Eduard Tolosa, Antonella Consiglio and Angel Raya
EMBO Mol Med 2012, 4(5), 380-395



The large diversity of tumor phenotypes may stem from oncogenic mutations arising in the stem, progenitor or precursor cell stages of different tissues. The authors show that the ultimate leukemia phenotype is influenced by the cellular origin as well as the the pathway of differentiation. Therefore, two therapeutic challenges must be addressed in certain types of leukemia - both the COCs and the CSCs must be eradicated for a successful therapy.


‘Hearts and bones’: the ups and downs of ‘plasticity’ in stem cell biology
Paola Bonfanti, Yann Barrandon and Giulio Cossu
EMBO Mol Med 2012, 4(5), 353-361



This review discusses the concept of "plasticity", defined here as the ability of a cell to change its fate in response to environmental signals. Historical and ethical views are given to better understand the modern concept of embryonic or induced stem cells reprogramming.


Diverging fates of cells of origin in acute and chronic leukaemia
Boris Kovacic, Andrea Hoelbl, Gabriele Litos, Memetcan Alacakaptan, Christian Schuster, Katrin M. Fischhuber, Marc A. Kerenyi, Gabriele Stengl, Richard Moriggl, Veronika Sexl, Hartmut Beug
EMBO Mol Med 2012, 4(4), 283-297



The large diversity of tumor phenotypes may stem from oncogenic mutations arising in the stem, progenitor or precursor cell stages of different tissues. The authors show that the ultimate leukemia phenotype is influenced by the cellular origin as well as the the pathway of differentiation. Therefore, two therapeutic challenges must be addressed in certain types of leukemia - both the COCs and the CSCs must be eradicated for a successful therapy.


Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells
Markus Eberl, Stefan Klingler, Doris Mangelberger, Andrea Loipetzberger, Helene Damhofer, Kerstin Zoidl, Harald Schnidar, Hendrik Hache, Hans-Christian Bauer, Flavio Solca, Cornelia Hauser-Kronberger, Alexandre N. Ermilov, Monique E. Verhaegen, Christopher K. Bichakjian, Andrzej A. Dlugosz, Wilfried Nietfeld, Maria Sibilia, Hans Lehrach, Christoph Wierling, Fritz Aberger
EMBO Mol Med 2012, 4(3), 218-233



The authors show that EGFR signaling is a valid drug target in Hedgehog-dependent cancers and provide a rationale for combination therapies based on simultaneous targeting of Hedgehog, EGFR and cooperation response genes including CXCR4 or FGF19.


Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia
Christian B. Jung, Alessandra Moretti, Michael Mederos y Schnitzler, Laura Iop, Ursula Storch, Milena Bellin, Tatjana Dorn, Sandra Ruppenthal, Sarah Pfeiffer, Alexander Goedel, Ralf J. Dirschinger, Melchior Seyfarth, Jason T. Lam, Daniel Sinnecker, Thomas Gudermann, Peter Lipp, Karl-Ludwig Laugwitz
EMBO Mol Med 2012, 4(3), 180-191



Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease that, under physical and emotional stress, leads to life-threatening arrhythmia followed by syncopes and sudden cardiac death at a young age in patients with structurally normal heart. In this study, the authors generated the first human model of CPVT.


Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb
Tomoko Kuwabara, Mohamedi N. Kagalwala, Yasuko Onuma, Yuzuru Ito, Masaki Warashina Kazuyuki Terashima, Tsukasa Sanosaka, Kinichi Nakashima, Fred H. Gage, Makoto Asashima
EMBO Mol Med 2011, 3(12), 742-754



Neural progenitor cells from the hippocampus and the olfactory bulb of type I and type II diabetic rats can be transplanted back into diabetic rats and produce insulin, demonstrating their potential as therapeutic agents. Upon transplantation into the pancreas, not only neuronal cells express transcription factors characteristic for pancreatic beta cells, but insulin level in plasma increases and glucose levels in blood stabilize.

Accompanying Closeup
Neural stem cells for diabetes cell-based therapy
Onur Basak, Hans Clevers
EMBO Mol Med 2011, 3(12), 698-700


Haematopoietic stem cell differentiation promotes the release of prominin-1/CD133-containing membrane vesicles—a role of the endocytic–exocytic pathway
Nicola Bauer, Michaela Wilsch-Bräuninger, Jana Karbanová, Ana-Violeta Fonseca, Doreen Strauss, Daniel Freund, Christoph Thiele, Wieland B. Huttner, Martin Bornhäuser, Denis Corbeil
EMBO Mol Med 2011, 3(7), 398-409



The authors highlighted the role of the endocytic-exocytic pathway in the release of prominin-1, which occurs concomitantly with cellular differentiation, and provide evidence for the intercellular communication between stem cells and their supporting feeder cells.


Quantitative tracking of T cell clones after haematopoietic stem cell transplantation
Ilgar Z. Mamedov, Olga V. Britanova, Dmitriy A. Bolotin, Anna V. Chkalina, Dmitriy B. Staroverov, Ivan V. Zvyagin, Alexey A. Kotlobay, Maria A. Turchaninova, Denis A. Fedorenko, Andrew A. Novik, George V. Sharonov, Sergey Lukyanov, Dmitriy M. Chudakov, Yuri B. Lebedev
EMBO Mol Med 2011, 3(4), 201-207



Autologous haematopoietic stem cell transplantation is successfully used to treat severe autoimmune diseases, but the mechanisms by which it resets the dysregulated immune system, remain poorly understood. Here, the authors report an optimized TCR profiling method by massive sequencing, use it to track the fate of T cell clones after transplantation and show that multiple clones not only survive, but form a new skewed and stable T cell receptor repertoire.


Integration profile of retroviral vector in gene therapy treated patients is cell-specific according to gene expression and chromatin conformation of target cell
Luca Biasco, Alessandro Ambrosi, Danilo Pellin, Cynthia Bartholomae, Immacolata Brigida, Maria Grazia Roncarolo, Clelia Di Serio, Christof von Kalle, Manfred Schmidt, Alessandro Aiuti
EMBO Mol Med 2011, 3(2), 89-101



Retroviral vectors have been used as effective tools to transfer therapeutic genes for the treatment of haematological inherited disorders. Here, the authors study the properties of genomic integration sites of a gammaretroviral vector in haematopoietic cells from GT-treated patients affected by ADA-SCID, treated either with mature lymphocytes or haematopoietic stem cells. This work provides crucial information for the follow up of current and future GT trials based on genetic modifications of haematopoietic cells.

Accompanying Closeup
Parachuting in the epigenome: the biology of gene vector insertion profiles in the context of clinical trials
Christopher Baum
EMBO Mol Med 2011, 3(2), 75-77


Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens
Kristen M. Smith, Alessandro Datti, Mayumi Fujitani, Natalie Grinshtein, Libo Zhang, Olena Morozova, Kim M. Blakely, Susan A. Rotenberg, Loen M. Hansford, Freda D. Miller, Herman Yeger, Meredith S. Irwin, Jason Moffat, Marco A. Marra, Sylvain Baruchel, Jeffrey L. Wrana, David R. Kaplan
EMBO Mol Med 2010, 2(9), 371-384



High-risk neuroblastoma (NB) survival in patients older than 1 year of age is 40%. For those patients, there is significant morbidity due to treatment-related toxicities. Using a high-throughput cell-based screening assay, the authors identified compounds that selectively target NB cancer stem cell-like tumor initiating cells while having little effect on normal stem cells. Based on this, a multicenter North American phase 1 study has opened to evaluate rapamycin in combination with vinblastine for pediatric solid tumors.


Correction of β-thalassemia major by gene transfer in haematopoietic progenitors of pediatric patients
Emanuela Anna Roselli, Riccardo Mezzadra, Marta Claudia Frittoli, Giulietta Maruggi, Erika Biral, Fulvio Mavilio, Fabrizio Mastropietro, Antonio Amato, Giovanni Tonon, Chiara Refaldi, Maria Domenica Cappellini, Marco Andreani, Guido Lucarelli, Maria Grazia Roncarolo, Sarah Marktel, Giuliana Ferrari
EMBO Mol Med 2010, 2(8), 315-328



β-Thalassemia leads to anemia and death in the first year of life unless regular transfusions are administered. So far, allogeneic bone marrow transplantation (BMT) is the only curative treatment, but it is limited to less than 25% of patients. Gene therapy, based on autologous transplantation of genetically corrected hematopoietic stem cells, represents a promising alternative for patients lacking a suitable donor. This study provides solid preclinical data of efficacy and safety of the GLOBE-based gene therapy approach to β-thalassemia.

Accompanying Closeup
Gaining the hard yard: pre-clinical evaluation of lentiviral-mediated gene therapy for the treatment of β-thalassemia
Michael D. Milsom, David A. Williams
EMBO Mol Med 2010, 2(8), 291-293


Regulation of liver regeneration by growth factors and cytokines
Friederike Böhm, Ulrike A. Köhler, Tobias Speicher, Sabine Werner
EMBO Mol Med 2010, 2(8), 294-305



The capability of the liver to fully regenerate after injury is a unique phenomenon essential for the maintenance of its important functions in the control of metabolism and xenobiotic detoxification. The regeneration process is histologically well described, but the genes that orchestrate liver regeneration have been only partially characterized. This review summarizes the results obtained by functional studies that have addressed the roles and mechanisms of action of growth factors and cytokines in liver regeneration after acute injury to this organ.


Pluripotent stem cells: private obsession and public expectation
Austin Smith
EMBO Mol Med 2010, 2(4), 113-116



Austin Smith gives us here his perception of pluripotency and its promises for medical research.


Molecular aging and rejuvenation of human muscle stem cells
Morgan E. Carlson, Charlotte Suetta, Michael J. Conboy, Per Aagaard, Abigail Mackey, Michael Kjaer, Irina Conboy
EMBO Mol Med 2009, 1(8-9), 381-391



The capacity of tissues to regenerate declines with age and eventually fails, leading to degenerative disorders and catastrophic organ failure. A textbook example is muscle wasting, accompanied by the loss of strength and agility in older individuals. This work uncovers the molecular culprits responsible for the lack of tissue maintenance and repair seen in old humans, and demonstrates that, as seen in mice, old human muscle stem cells are actually capable of productive regeneration, but are inhibited by their own muscle to do so.


Design principles of pluripotency
Austin Smith
EMBO Mol Med 2009, 1(5), 251-254



Pluripotency is the capacity of individual cells to initiate all lineages of the mature organism in a flexible manner directed by signals in the embryo or cell culture environment. It is the keystone of mammalian development and of embryonic stem cell biology. A pluripotent cell has no predetermined programme; it is a blank slate.


Epidermal stem cell diversity and quiescence
Fiona M. Watt, Kim B. Jensen
EMBO Mol Med 2009, 1(5), 260-267



Mammalian epidermis is maintained by self-renewal of stem cells and terminal differentiation of their progeny. New data reveal a diversity amongst stem cells that was previously unrecognized. Different stem cell populations have different locations and differ in whether they are quiescent or actively cycling. During normal epidermal homeostasis, each stem cell population feeds a restricted number of differentiated lineages. However, in response to injury or genetic manipulation the different pools of stem cells demonstrate multi-lineage differentiation ability.


Searching for adult stem cells in the intestine
Hans Clevers
EMBO Mol Med 2009, 1(5), 255-259



The epithelium of the small intestine is the most rapidly self-renewing tissue of mammals. Vigorous proliferation of progenitor cells occurs in crypts, while their differentiated offspring leaves the crypts and travels up the flanks of the villi to suffer death by apoptosis at villus tips 3 days later. The crypts have long been assumed to harbor functional stem cells. Yet, the absence of unique molecular markers has hampered their definitive identification.


Awaking stem cells from dormancy: growing old and fighting cancer
Andrea Viale, Pier G. Pelicci
EMBO Mol Med 2009, 1(2), 88-91



It is generally accepted that a distinguishing property of stem cells, as compared to their more differentiated progenitors, is that of infrequent division, often referred to as 'quiescence'. As regards hematopoietic stem cells (HSC), their resistance to antiproliferative drugs supports this notion. Maintenance of quiescence is thought to be critical for the preservation of HSCs' function.

SEARCH

SEARCH BY CITATION