STEM CELLS

Cover image for Vol. 34 Issue 7

July 2016

Volume 34, Issue 7

Pages i–Viii, 1709–1995

  1. Issue Information

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. You have free access to this content
      Issue Information (pages i–Viii)

      Version of Record online: 4 JUL 2016 | DOI: 10.1002/stem.2156

  2. Translational and Clinical Research

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. You have free access to this content
      Concise Review: Stem Cell Trials Using Companion Animal Disease Models (pages 1709–1729)

      Andrew M. Hoffman and Steven W. Dow

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/stem.2377

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      Companion animal diseases (reviewed in Table 1) have the potential to serve as realistic models of human disease, as they more closely approximate the natural history, symptoms, pathology, biomarkers, therapeutic responses, tolerance to therapies, and survival characteristics of analogous human conditions. Stem cell trials in companion animal disease models are, therefore, of interest as translational systems in regenerative medicine. We reviewed the study design, manufacturing, endpoints, safety, and efficacy data from stem cell trials in dogs and cats between the years of 2008-2015 (n = 19) (Table 2). Most clinical trials were open label design involving MSC (see Cells Evaluated), informing safety, route of administration, feasibility of protocols with modest power to evaluate efficacy. Overall safety was excellent, and patients showed responses that exceeded expectations based on baseline, historical, or interventional (placebo) controls. Companion animal disease models have potential to inform hypotheses concerning stem cell trials in humans. Improved rigor in study design and manufacturing will unmask the full potential of this approach to benefit humans and animals.

  3. Cancer Stem Cells

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. Rac1 GTPase Promotes Interaction of Hematopoietic Stem/Progenitor Cell with Niche and Participates in Leukemia Initiation and Maintenance in Mouse (pages 1730–1741)

      Shuying Chen, Huan Li, Shouyun Li, Jing Yu, Min Wang, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao and Jianxiang Wang

      Version of Record online: 27 MAR 2016 | DOI: 10.1002/stem.2348

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      By establishing an active Rac1 associated acute myeloid leukemia (AML) model via expression of Rac1-V12 cooperated with AML1-ETO9a (AE9a) in mouse hematopoietic stem/progenitor cells, we show that compared with AE9a alone, Rac1-V12 cooperated with AE9a (AER) drives an AML with a short latency, demonstrating that activation of Rac1 GTPase in mice promotes AML development. The mechanism of this AML promotion is by a better homing and lodging of leukemia cells in niche, which further enhancing their colony formation, quiescence and preventing leukemia cells from apoptosis. Further study shows that an inhibitor targeting activated Rac1 can increase the efficacy of chemotherapeutic agents to leukemia cells.

  4. Embryonic Stem Cells/Induced Pluripotent Stem Cells

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. ST8SIA4-Dependent Polysialylation is Part of a Developmental Program Required for Germ Layer Formation from Human Pluripotent Stem Cells (pages 1742–1752)

      Ryan P. Berger, Yu Hua Sun, Michael Kulik, Jin Kyu Lee, Alison V. Nairn, Kelley W. Moremen, Michael Pierce and Stephen Dalton

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/stem.2379

    2. Lineage-Specific Early Differentiation of Human Embryonic Stem Cells Requires a G2 Cell Cycle Pause (pages 1765–1775)

      Jennifer J. Van Oudenhove, Rodrigo A. Grandy, Prachi N. Ghule, Roxana del Rio, Jane B. Lian, Janet L. Stein, Sayyed K. Zaidi and Gary S. Stein

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/stem.2352

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      Early after induction of differentiation to certain lineages there is an increase in nuclear WEE1 that phosphorylates the CDK1/cyclin complex at Y15, inhibiting progression into mitosis and forcing cells to pause in G2. This pause is seen in mesendoderm, mesoderm, and endoderm differentiation but is only required for endoderm differentiation.

    3. Rbm24 Regulates Alternative Splicing Switch in Embryonic Stem Cell Cardiac Lineage Differentiation (pages 1776–1789)

      Tao Zhang, Yu Lin, Jing Liu, Zi Guan Zhang, Wei Fu, Li Yan Guo, Lei Pan, Xu Kong, Meng Kai Zhang, Ying Hua Lu, Zheng Rong Huang, Qiang Xie, Wei Hua Li and Xiu Qin Xu

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/stem.2366

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      Rbm24 controls ESC lineage differentiation by a splicing-mediated regulatory mechanism. (a) Forced expression of Rbm24 promotes cardiac lineage specification from ESCs. (b) Rbm24 is a major splicing factor regulating alternative splicing events important in ESC cardiac differentiation. (c) Rbm24 decreased the expression of ESC-specific exon 5 and increased the expression of tissue-specific exon 6 of Tpm1; Knockdown of ESC-specific the Tpm1 isoform markedly affected the maintenance of ESC pluripotency. Results suggest that Rbm24 could reduce ESC pluripotency by switching splicing of the pluripotency transcripts toward tissue-specific isoforms.

    4. Different Concentrations of FGF Ligands, FGF2 or FGF8 Determine Distinct States of WNT-Induced Presomitic Mesoderm (pages 1790–1800)

      Smita Sudheer, Jinhua Liu, Matthias Marks, Frederic Koch, Anna Anurin, Manuela Scholze, Anna Dorothea Senft, Lars Wittler, Karol Macura, Phillip Grote and Bernhard G. Herrmann

      Version of Record online: 18 APR 2016 | DOI: 10.1002/stem.2371

  5. Regenerative Medicine

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. Silencing of Antichondrogenic MicroRNA-221 in Human Mesenchymal Stem Cells Promotes Cartilage Repair In Vivo (pages 1801–1811)

      Andrea Lolli, Roberto Narcisi, Elisabetta Lambertini, Letizia Penolazzi, Marco Angelozzi, Nicole Kops, Simona Gasparini, Gerjo J.V.M. van Osch and Roberta Piva

      Version of Record online: 27 MAR 2016 | DOI: 10.1002/stem.2350

    2. Intravenous Transplantation of Mesenchymal Progenitors Distribute Solely to the Lungs and Improve Outcomes in Cervical Spinal Cord Injury (pages 1812–1825)

      Seok Voon White, Chris E. Czisch, May H. Han, Christine D. Plant, Alan R. Harvey and Giles W. Plant

      Version of Record online: 4 APR 2016 | DOI: 10.1002/stem.2364

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      Mesenchymal progenitor cells intravenously injected after cervical spinal cord injury are found in the lungs. Luc-GFP+ mesenchymal progenitor cells were intravenously injected at D1, D3, D7, D10 or D14 after C5 unilateral contusion or hemisection spinal cord injury. (A) Bioluminescence imaging showed that intravenous injected cells traveled to the lung region regardless of injury type or time of injection. (B, C) A subset of mice receiving C5 unilateral contusion spinal cord injury with mesenchymal progenitor cells intravenously injected at D1 was sacrificed at 6 hours and GFP+ cells were found in the lungs of these mice. Scale bar = 50 μm.

    3. Paracrine Engineering of Human Explant-Derived Cardiac Stem Cells to Over-Express Stromal-Cell Derived Factor 1α Enhances Myocardial Repair (pages 1826–1835)

      Everad L. Tilokee, Nicholas Latham, Robyn Jackson, Audrey E. Mayfield, Bin Ye, Seth Mount, Buu-Khanh Lam, Erik J. Suuronen, Marc Ruel, Duncan J. Stewart and Darryl R. Davis

      Version of Record online: 21 APR 2016 | DOI: 10.1002/stem.2373

    4. Mesenchymal Stem Cells Induce Suppressive Macrophages Through Phagocytosis in a Mouse Model of Asthma (pages 1836–1845)

      Faouzi Braza, Stéphanie Dirou, Virginie Forest, Vincent Sauzeau, Dorian Hassoun, Julie Chesné, Marie-Aude Cheminant-Muller, Christine Sagan, Antoine Magnan and Patricia Lemarchand

      Version of Record online: 14 MAR 2016 | DOI: 10.1002/stem.2344

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      Lung macrophages have been cell-sorted from lung cell suspensions, 24 hours after intravenous injection of PKH26 + mesenchymal stem cells (MSCs). PKH26 staining is characterized by incorporation of red fluorescent molecules into the cell membrane and induces intense and reproducible fluorescence. Lung macrophages show PKH26 + (red) labeling, suggesting that they had in vivo phagocyted the PKH26 + MSCs.

  6. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. You have full text access to this OnlineOpen article
      MiR-211/STAT5A Signaling Modulates Migration of Mesenchymal Stem Cells to Improve its Therapeutic Efficacy (pages 1846–1858)

      Xinyang Hu, Panpan Chen, Yan Wu, Kan Wang, Yinchuan Xu, Han Chen, Ling Zhang, Rongrong Wu, Keith A. Webster, Hong Yu, Wei Zhu and Jian'an Wang

      Version of Record online: 19 MAY 2016 | DOI: 10.1002/stem.2391

  7. Tissue-Specific Stem Cells

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. Kras is Required for Adult Hematopoiesis (pages 1859–1871)

      Alisa Damnernsawad, Guangyao Kong, Zhi Wen, Yangang Liu, Adhithi Rajagopalan, Xiaona You, Jinyong Wang, Yun Zhou, Erik A. Ranheim, Hongbo R. Luo, Qiang Chang and Jing Zhang

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/stem.2355

    2. You have full text access to this OnlineOpen article
      LSD1 Mediates Neuronal Differentiation of Human Fetal Neural Stem Cells by Controlling the Expression of a Novel Target Gene, HEYL (pages 1872–1882)

      Kazumi Hirano and Masakazu Namihira

      Version of Record online: 27 MAR 2016 | DOI: 10.1002/stem.2362

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      LSD1 mediates neuronal differentiation of human fetal neural stem cells (hfNSCs) by controlling the expression of HEYL (A): The cells treated with or without LSD1 inhibitor were stained with antibody against βIII-tubulin. ** p < .01. (B): Schematic representation of the proximal 5′ region (∼ -1kb) of the human HEYL locus and designed primer sets (Primer1-3). ChIP assays for hfNSC after induction of differentiation were performed, followed by real-time PCR with the proper primer sets in the HEYL promoter. *, p < .05; **, p < .01; ***, p < .005. (C): The cells overexpressing HEYL were stained with antibody against βIII-tubulin. ****, p < .001. (D): Scheme for neuronal differentiation through histone demethylation of LSD1 in hfNSC. At the induction of neuronal differentiation, LSD1 associates with a site close to the RBP-J binding region, demethylates H3K4 methylation on the HEYL promoter, and represses its expression. Because of the repression of HEYL expression by LSD1, hfNSCs are induced to differentiate into excitatory and inhibitory neurons. On the other hand, LSD1 inhibitor treatment blocks the effect of LSD1 on the HEYL promoter resulting in high levels of HEYL, which may repress the expression of genes such as CTIP2 and DLX5 directly or indirectly, and prevent neuronal differentiation.

    3. Targeting IκB kinase β in Adipocyte Lineage Cells for Treatment of Obesity and Metabolic Dysfunctions (pages 1883–1895)

      Robert N. Helsley, Yipeng Sui, Se-Hyung Park, Zun Liu, Richard G. Lee, Beibei Zhu, Philip A. Kern and Changcheng Zhou

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/stem.2358

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      Working model of the role of IκB kinase β (IKKβ) signaling in adipocyte lineage cells in obesity. (A): Under normal feeding condition, the IKKβ/NF-κB signaling is maintained at basal activity. (B): Under high-fat feeding condition, overnutrition (e.g., excess free fatty acids) activates IKKβ, leading to increased adipogenesis and inflammation. (C): In the current study, pharmacological inhibition or genetic deletion of IKKβ in adipocyte lineage cells impairs adipogenesis and protects mice from high-fat diet-induced obesity and metabolic dysfunctions

    4. Foxi3 Deficiency Compromises Hair Follicle Stem Cell Specification and Activation (pages 1896–1908)

      Vera Shirokova, Leah C. Biggs, Maria Jussila, Takahiro Ohyama, Andrew K. Groves and Marja L. Mikkola

      Version of Record online: 4 APR 2016 | DOI: 10.1002/stem.2363

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      Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses (pages 1909–1921)

      Laura Chiossone, Romana Conte, Grazia Maria Spaggiari, Martina Serra, Cristina Romei, Francesca Bellora, Flavio Becchetti, Antonio Andaloro, Lorenzo Moretta and Cristina Bottino

      Version of Record online: 14 APR 2016 | DOI: 10.1002/stem.2369

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      Mesenchymal stromal cells (MSC) induce the generation of a novel subset of alternatively activated macrophages (MMSC), via the release of PGE2. MMSC are characterized by high expression of CD14, CD16, CD206, HLA-II, CD11b, CD163, and CD209 and secrete high amounts of IL-1β, IL-10, and TGF-β. These cytokines contribute to the immunoregulatory properties of MMSC. Interacting with autologous activated NK cells, MMSC inhibit both the expression of activating molecules such as NKp44, CD69, and CD25 and the production of IFNγ. Moreover, MMSC inhibit the proliferation of CD8+ T cells and induce the expansion of regulatory T cells (Treg). LPS revert the phenotypic and functional features of MMSC to those of M1 immunostimulatory/proinflammatory macrophages.

    6. You have full text access to this OnlineOpen article
      Tumor Necrosis Factor α Regulates Endothelial Progenitor Cell Migration via CADM1 and NF-kB (pages 1922–1933)

      Anthony R. Prisco, Brian R. Hoffmann, Catherine C. Kaczorowski, Chris McDermott-Roe, Timothy J. Stodola, Eric C. Exner and Andrew S. Greene

      Version of Record online: 4 MAR 2016 | DOI: 10.1002/stem.2339

  8. Translational and Clinical Research

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. You have full text access to this OnlineOpen article
    2. A Novel Therapeutic Approach Using Mesenchymal Stem Cells to Protect Against Mycobacterium abscessus (pages 1957–1970)

      Jong-Seok Kim, Sang-Ho Cha, Woo Sik Kim, Seung Jung Han, Seung Bin Cha, Hong Min Kim, Kee Woong Kwon, So Jeong Kim, Hong-Hee Choi, Jienny Lee, Sang-Nae Cho, Won-Jung Koh, Yeong-Min Park and Sung Jae Shin

      Version of Record online: 27 MAR 2016 | DOI: 10.1002/stem.2353

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      Effects of aminoguanidine on MSC-induced M. abs-R clearance in mice. (A) Schematic diagram of the experimental design. (B) C57BL/6J mice were infected with an aerosolized strain of M. abs-R (1.6 × 107 CFUs/mouse), and MSCs (2.5 × 105 cells/mouse) were administered by intravenous injection at one day post-infection. Aminoguanidine was administered at a dose of 0.25% ad libitum in the drinking water each day, starting one day post-infection. The data are presented as the means ± SEM of two experiments (**, p < .01 and ***, p < .001). (C) The effects of MSCs on iNOS expression in the lungs of M. abs-R-infected mice. Immunohistochemistry was performed as described in “Materials and Methods” (scale bar = 100 μm). (E) C57BL/6J mice were infected with an aerosolized strain of M. abs-R (1.6 × 107 CFUs/mouse), and Cox-2−/− and iNOS−/− MSCs (2.5 × 105 cells/mouse) were administered by intravenous injection at one day post-infection. After 10 day after infection, bacterial CFUs were measured at lung and spleen as described in “Materials and Methods.” The results are expressed as the mean estimated CFU ± SEM from the lung samples of five to six mice in two independent experiments. (D) Representative immunohistochemistry staining of iNOS and F4/80 (scale bar = 10 μm).

    3. You have full text access to this OnlineOpen article
      In Vivo Interleukin-13-Primed Macrophages Contribute to Reduced Alloantigen-Specific T Cell Activation and Prolong Immunological Survival of Allogeneic Mesenchymal Stem Cell Implants (pages 1971–1984)

      Chloé J. Hoornaert, Evi Luyckx, Kristien Reekmans, Maxime Dhainaut, Caroline Guglielmetti, Debbie Le Blon, Dearbhaile Dooley, Erik Fransen, Jasmijn Daans, Louca Verbeeck, Alessandra Quarta, Nathalie De Vocht, Evi Lemmens, Herman Goossens, Annemie Van der Linden, Valerie D. Roobrouck, Catherine Verfaillie, Sven Hendrix, Muriel Moser, Zwi N. Berneman and Peter Ponsaerts

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/stem.2360

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      Upon transplantation of IL13-engineered MSCs into allogeneic mice, local IL13 production modulated both innate and adaptive immune responses, ultimately resulting in prolonged MSC allograft survival. (A): FVB mouse-derived MSC-Luc/eGFP and MSC-Luc/eGFP/IL13 implants in the muscle or brain of C57BL/6 mice. Expression of Arg1, a marker of alternative M2a activation, was restricted to F4/80+ macrophages infiltrating IL13-producing MSC grafts. (B): T cells from naive, FVB MSC-transplanted or FVB MSC-IL13-transplanted C57BL/6 mice were analyzed by flow cytometry, with or without prior FVB MSC stimulation. IL13-expressing MSC allografts induced significantly fewer alloreactive CD8+ T cells than wildtype MSC allografts. *p<0.05; ***p<0.001 (C+D): Quantitative analysis of in vivo bioluminescence imaging of intramuscular (panel C) and intracerebral (panel D) FVB MSC-Luc/eGFP or FVB MSC-Luc/eGFP/IL13 allografts in C57BL/6 mice. Background radiance is demarcated by the gray area. IL13-expressing MSC allografts display a prolonged survival in both muscle and brain tissue of immune competent mice. **p<0.01 Abbreviations: MSC, mesenchymal stem cell; IL13, interleukin-13; Luc, firefly luciferase; eGFP, enhanced green fluorescent protein; Arg1, arginase-1.

  9. Embryonic Stem Cells/Induced Pluripotent Stem Cells

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor
    1. A miR-372/let-7 Axis Regulates Human Germ Versus Somatic Cell Fates (pages 1985–1991)

      Nam D. Tran, Michael Kissner, Deepa Subramanyam, Ronald J. Parchem, Diana J. Laird and Robert H. Blelloch

      Version of Record online: 17 MAY 2016 | DOI: 10.1002/stem.2378

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      Let-7 and miR-294 antagonistically regulate somatic versus germline fates through their influence on multiple cellular pathways.

  10. Letters to the Editor

    1. Top of page
    2. Issue Information
    3. Translational and Clinical Research
    4. Cancer Stem Cells
    5. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    6. Regenerative Medicine
    7. Stem Cell Technology: Epigenetics, Genomics, Proteomics and Metabonomics
    8. Tissue-Specific Stem Cells
    9. Translational and Clinical Research
    10. Embryonic Stem Cells/Induced Pluripotent Stem Cells
    11. Letters to the Editor

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