Jun 08, 2021

Volume 16Issue 6p1391-1644
Open Access
Cover The cover image portrays a tree, representing developing stem cell-based interventions, and a Möbius band, implying the nature of regulations with their three key elements: research and care, safety and efficacy, and hope and concerns. This illustration was inspired by the reverse view of “Ginevra de’ Benci” (1474/1478) by Leonardo da Vinci. See Takashima, Morrison, and Minari (1425–1434). Cover design by Mindy Takamiya....
Cover The cover image portrays a tree, representing developing stem cell-based interventions, and a Möbius band, implying the nature of regulations with their three key elements: research and care, safety and efficacy, and hope and concerns. This illustration was inspired by the reverse view of “Ginevra de’ Benci” (1474/1478) by Leonardo da Vinci. See Takashima, Morrison, and Minari (1425–1434). Cover design by Mindy Takamiya.




  • ISSCR Guidelines for Stem Cell Research and Clinical Translation: The 2021 update

    • Robin Lovell-Badge,
    • Eric Anthony,
    • Roger A. Barker,
    • Tania Bubela,
    • Ali H. Brivanlou,
    • Melissa Carpenter,
    • R. Alta Charo,
    • Amander Clark,
    • Ellen Clayton,
    • Yali Cong,
    • George Q. Daley,
    • Jianping Fu,
    • Misao Fujita,
    • Andy Greenfield,
    • Steve A. Goldman,
    • Lori Hill,
    • Insoo Hyun,
    • Rosario Isasi,
    • Jeffrey Kahn,
    • Kazuto Kato,
    • Jin-Soo Kim,
    • Jonathan Kimmelman,
    • Jürgen A. Knoblich,
    • Debra Mathews,
    • Nuria Montserrat,
    • Jack Mosher,
    • Megan Munsie,
    • Hiromitsu Nakauchi,
    • Luigi Naldini,
    • Gail Naughton,
    • Kathy Niakan,
    • Ubaka Ogbogu,
    • Roger Pedersen,
    • Nicolas Rivron,
    • Heather Rooke,
    • Janet Rossant,
    • Jeff Round,
    • Mitinori Saitou,
    • Douglas Sipp,
    • Julie Steffann,
    • Jeremy Sugarman,
    • Azim Surani,
    • Jun Takahashi,
    • Fuchou Tang,
    • Leigh Turner,
    • Patricia J. Zettler,
    • Xiaomei Zhai
    The updated Guidelines for Stem Cell Research and Clinical Translation describe the ethical principles and best practices for basic, translational, and clinical research involving stem cells and human embryos. The updated Guidelines include new recommendations to address the recent scientific advances involving embryos, stem cell-based embryo models, chimeras, organoids, and genome editing.
  • ISSCR guidelines for the transfer of human pluripotent stem cells and their direct derivatives into animal hosts

    • Insoo Hyun,
    • Ellen Wright Clayton,
    • Yali Cong,
    • Misao Fujita,
    • Steven A. Goldman,
    • Lori R. Hill,
    • Nuria Monserrat,
    • Hiromitsu Nakauchi,
    • Roger A. Pedersen,
    • Heather M. Rooke,
    • Jun Takahashi,
    • Jürgen A. Knoblich
    The newly revised 2021 ISSCR Guidelines for Stem Cell Research and Clinical Translation includes scientific and ethical guidance for the transfer of human pluripotent stem cells and their direct derivatives into animal models. In this white paper, the ISSCR subcommittee that drafted these guidelines for research involving the use of nonhuman embryos and postnatal animals explains and summarizes their recommendations.
  • Human embryo research, stem cell-derived embryo models and in vitro gametogenesis: Considerations leading to the revised ISSCR guidelines

    • Amander T. Clark,
    • Ali Brivanlou,
    • Jianping Fu,
    • Kazuto Kato,
    • Debra Mathews,
    • Kathy K. Niakan,
    • Nicolas Rivron,
    • Mitinori Saitou,
    • Azim Surani,
    • Fuchou Tang,
    • Janet Rossant
    In this perspective, Rossant, Clark, and colleagues outline the process and deliberations that led to the updated ISSCR Guidelines for stem cell research involving the 14-Day rule, stem cell-based embryo models, and in vitro gametogenesis.
  • Reflection on the enactment and impact of safety laws for regenerative medicine in Japan

    • Kayo Takashima,
    • Michael Morrison,
    • Jusaku Minari
    In this article, Takashima, Morrison, and Minari examine the origin and implications of Japan’s Act on the Safety of Regenerative Medicine. The article describes the development of this regulatory framework to safely promote the clinical development of stem cell-based interventions, identifies scope for potential improvement, and highlights lessons for other jurisdictions.
  • Unproven stem cell interventions: A global public health problem requiring global deliberation

    • Zubin Master,
    • Kirstin R.W. Matthews,
    • Mohamed Abou-el-Enein
    In this article, Master, Matthews, and Abou-el-Enein argue that the World Health Organization (WHO) should establish an Expert Advisory Committee on Regenerative Medicine to address the global problem of clinics selling unproven stem cell interventions (SCIs). The WHO committee can develop harmonized standards, promote responsible access to cell-based therapeutics for patients, and create an information campaign to address public misinformation.
  • Balancing serendipity and reproducibility: Pluripotent stem cells as experimental systems for intellectual and developmental disorders

    • Nickesha C. Anderson,
    • Pin-Fang Chen,
    • Kesavan Meganathan,
    • Wardiya Afshar Saber,
    • Andrew J. Petersen,
    • Anita Bhattacharyya,
    • Kristen L. Kroll,
    • Mustafa Sahin
    • on behalf of the Cross-IDDRC Human Stem Cell Working Group
    In this article, Anderson et al. review 58 research articles to assess the state of intellectual and developmental disabilities (IDDs) research utilizing iPSC-derived neural cells. Major sources of biological and technical variability are identified, and potential areas of improvement are proposed. To define reproducible cellular phenotypes linked to IDDs, the stem cell research community needs to develop shared standards, approaches, and benchmarks.


  • Study of inherited thrombocytopenia resulting from mutations in ETV6 or RUNX1 using a human pluripotent stem cell model

    • Sara Borst,
    • Catriana C. Nations,
    • Joshua G. Klein,
    • Giulia Pavani,
    • Jean Ann Maguire,
    • Rodney M. Camire,
    • Michael W. Drazer,
    • Lucy A. Godley,
    • Deborah L. French,
    • Mortimer Poncz,
    • Paul Gadue
    Borst et al. report the first ETV6-mutant iPSC line to model inherited thrombocytopenia with predisposition for hematologic malignancy. Using CRISPR-Cas9 technology, they generate sets of isogenic iPSC lines with patient-specific mutations in ETV6 or RUNX1, both of which lead to thrombocytopenia and high cancer risk. Disparate phenotypes between the two genotypes are identified, suggesting the mechanism of disease is different.
  • Antitumor effects of iPSC-based cancer vaccine in pancreatic cancer

    • Xiaoming Ouyang,
    • Yu Liu,
    • Yang Zhou,
    • Jing Guo,
    • Tzu-Tang Wei,
    • Chun Liu,
    • Bomi Lee,
    • Binbin Chen,
    • Angela Zhang,
    • Kerriann M. Casey,
    • Lin Wang,
    • Nigel G. Kooreman,
    • Aida Habtezion,
    • Edgar G. Engleman,
    • Joseph C. Wu
    In this article, Wu and colleagues demonstrate that an iPSC-based cancer vaccine, comprised of iPSCs and CpG, stimulated cytotoxic T cell and B cell responses, reduced immune-suppressive Treg cells, and prevented tumor formation in mice injected with pancreatic ductal adenocarcinoma (PDAC) cells. The “iPSC-cancer signature genes” are overexpressed among iPSC lines, PDAC cells, and multiple human cancers. These results support further studies of iPSC-based cancer vaccine for treatment of PDAC.


  • Human iPSC-based neurodevelopmental models of globoid cell leukodystrophy uncover patient- and cell type-specific disease phenotypes

    • Elisabeth Mangiameli,
    • Anna Cecchele,
    • Francesco Morena,
    • Francesca Sanvito,
    • Vittoria Matafora,
    • Angela Cattaneo,
    • Lucrezia della Volpe,
    • Daniela Gnani,
    • Marianna Paulis,
    • Lucia Susani,
    • Sabata Martino,
    • Raffaella Di Micco,
    • Angela Bachi,
    • Angela Gritti
    In this article, Mangiameli et al. study the impact of GALC deficiency and lentiviral vector-mediated GALC rescue/overexpression in GLD hiPSC-derived neural progenitors and their neuronal/glial progeny. The study uncovers unforeseen mutation- and cell type-specific early pathogenic events (i.e. lipid unbalance and activation of a senescence program) that may contribute to GLD neuropathology along with psychosine storage, with important therapeutic implications.
  • A eutherian-specific microRNA controls the translation of Satb2 in a model of cortical differentiation

    • Manuella Martins,
    • Silvia Galfrè,
    • Marco Terrigno,
    • Luca Pandolfini,
    • Irene Appolloni,
    • Keagan Dunville,
    • Andrea Marranci,
    • Milena Rizzo,
    • Alberto Mercatanti,
    • Laura Poliseno,
    • Francesco Morandin,
    • Marco Pietrosanto,
    • Manuela Helmer-Citterich,
    • Paolo Malatesta,
    • Robert Vignali,
    • Federico Cremisi
    In this article, Cremisi and colleagues show that post-transcriptional mechanisms are involved in controlling key functional aspects of SATB2-expressing cortical neurons. They show that mir-541, a eutherian-specific miRNA, delays SATB2 protein production in an in vitro model of cortical cell differentiation. These results may explain the heterochronic shift of SATB2 appearance in the eutherian compared with the metatherian cortex.
  • Identification of bioactive metabolites in human iPSC-derived dopaminergic neurons with PARK2 mutation: Altered mitochondrial and energy metabolism

    • Justyna Okarmus,
    • Jesper F. Havelund,
    • Matias Ryding,
    • Sissel I. Schmidt,
    • Helle Bogetofte,
    • Rachel Heon-Roberts,
    • Richard Wade-Martins,
    • Sally A. Cowley,
    • Brent J. Ryan,
    • Nils J. Færgeman,
    • Poul Hyttel,
    • Morten Meyer
    In this article, Okarmus and colleagues show that loss-of-function mutations in the PARK2 gene (parkin) leads to metabolic dysregulation. Changes in the metabolome of human iPSC-derived neurons with such mutations were accompanied by altered mitochondrial and energy homeostasis, increased oxidative stress, and a reduced anti-oxidative response. These findings represent a significant contribution to our understanding of Parkinson's disease pathogenesis.
  • Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations

    • Shio Mitsuzawa,
    • Naoki Suzuki,
    • Tetsuya Akiyama,
    • Mitsuru Ishikawa,
    • Takefumi Sone,
    • Jiro Kawada,
    • Ryo Funayama,
    • Matsuyuki Shirota,
    • Hiroaki Mitsuhashi,
    • Satoru Morimoto,
    • Kensuke Ikeda,
    • Tomomi Shijo,
    • Akiyuki Ohno,
    • Naoko Nakamura,
    • Hiroya Ono,
    • Risako Ono,
    • Shion Osana,
    • Tadashi Nakagawa,
    • Ayumi Nishiyama,
    • Rumiko Izumi,
    • Shohei Kaneda,
    • Yoshiho Ikeuchi,
    • Keiko Nakayama,
    • Teruo Fujii,
    • Hitoshi Warita,
    • Hideyuki Okano,
    • Masashi Aoki
    A novel modulatory gene PHOX2B decreased in human iPSC-derived MNs with TARDBP mutations and PHOX2B knockdown reduced neurite length and impaired motor functions in vivo and vitro. PHOX2B is known that highly express in other type of neurons maintained after the progression of ALS. Collectively, TARDBP mutations induced loss of axonal resilience, an important ALS-related phenotype, is mediated by PHOX2B downregulation.
  • Human induced pluripotent stem cell-derived atrial cardiomyocytes carrying an SCN5A mutation identify nitric oxide signaling as a mediator of atrial fibrillation

    • Liang Hong,
    • Meihong Zhang,
    • Olivia Thao Ly,
    • Hanna Chen,
    • Arvind Sridhar,
    • Erin Lambers,
    • Brandon Chalazan,
    • Seock-Won Youn,
    • Mark Maienschein-Cline,
    • Leonid Feferman,
    • Sang-Ging Ong,
    • Joseph C. Wu,
    • Jalees Rehman,
    • Dawood Darbar
    Hong et al. showed that patient-specific iPSC-aCMs exhibited striking electrophysiological phenotype of an AF-linked mutation that produced minimal changes in heterologous expression system, and discovered a link between enhanced late sodium currents (INa,L), transcriptional regulation of NO signaling, and triggered AF. These findings not only provide insights into underlying cellular mechanisms of AF-linked mutations but also highlight potential mechanism-based therapies for this common arrhythmia.
  • A regulatory role for CHD4 in maintenance of the spermatogonial stem cell pool

    • Shenae L. Cafe,
    • David A. Skerrett-Byrne,
    • Camila Salum De Oliveira,
    • Brett Nixon,
    • Melissa J. Oatley,
    • Jon M. Oatley,
    • Tessa Lord
    In this article, Lord and colleagues show that the remodeling protein CHD4 is highly expressed in spermatogonial stem cells (SSCs), and is functionally required for SSC maintenance. The authors demonstrate that CHD4 interacts with the NuRD complex and SALL4 to activate expression of “self-renewal” genes, such as Gfra1.
  • Photobiomodulation therapy for hair regeneration: A synergetic activation of β-CATENIN in hair follicle stem cells by ROS and paracrine WNTs

    • Huan Jin,
    • Zhengzhi Zou,
    • Haocai Chang,
    • Qi Shen,
    • Lingfeng Liu,
    • Da Xing
    Jin et al. provide evidence of the molecular mechanism that PBMT promotes hair growth. PBMT activates HFSCs to promote hair regeneration through increasing β-catenin expression, which is involved in the collaborative action of PBMT-induced ROS in HFSCs and PBMT-induced Wnt secretion in skin-derived precursors.
  • Neuroglian regulates Drosophila intestinal stem cell proliferation through enhanced signaling via the epidermal growth factor receptor

    • Martin Resnik-Docampo,
    • Kathleen M. Cunningham,
    • S. Mateo Ruvalcaba,
    • Charles Choi,
    • Vivien Sauer,
    • D. Leanne Jones
    In this article, Jones and colleagues demonstrate that Neuroglian (Nrg) is expressed in intestinal stem cells (ISCs) and enteroblasts of the Drosophila midgut, where it regulates ISC proliferation via the EGFR. Furthermore, data suggest that increased Nrg expression during aging contributes to ISC proliferation and intestinal dysplasia. These findings suggest a role for Nrg-EGFR signaling in the intestine, which could be implicated in age-related disease.
  • Megakaryocyte progenitor cell function is enhanced upon aging despite the functional decline of aged hematopoietic stem cells

    • Donna M. Poscablo,
    • Atesh K. Worthington,
    • Stephanie Smith-Berdan,
    • E. Camilla Forsberg
    Poscablo et al. explored age-related changes to hematopoietic stem cell and megakaryocyte progenitor (MkP) function. They found an unexpected gain of in vitro expansion and in vivo reconstitution potential of MkPs upon aging. These functional changes were accompanied by differences in transcriptome profiles between young and old MkPs, suggesting progenitor cell mechanisms contributing to hematopoietic aging.


  • Hematopoietic stem cells retain functional potential and molecular identity in hibernation cultures

    • Caroline A. Oedekoven,
    • Miriam Belmonte,
    • Daniel Bode,
    • Fiona K. Hamey,
    • Mairi S. Shepherd,
    • James Lok Chi Che,
    • Grace Boyd,
    • Craig McDonald,
    • Serena Belluschi,
    • Evangelia Diamanti,
    • Hugo P. Bastos,
    • Katherine S. Bridge,
    • Berthold Göttgens,
    • Elisa Laurenti,
    • David G. Kent
    In this study, the groups of David Kent and Elisa Laurenti show that fully functional mouse and human hematopoietic stem cells (HSCs) can be kept in a non-dividing state outside of their native microenvironment. Single-cell transplantations and RNA sequencing demonstrate a high degree of similarity to freshly isolated HSCs, but also identify molecular networks involved in HSC resilience.
  • An integrated analysis of human myeloid cells identifies gaps in in vitro models of in vivo biology

    • Nadia Rajab,
    • Paul W. Angel,
    • Yidi Deng,
    • Jennifer Gu,
    • Vanta Jameson,
    • Mariola Kurowska-Stolarska,
    • Simon Milling,
    • Chris M. Pacheco,
    • Matt Rutar,
    • Andrew L. Laslett,
    • Kim-Anh Lê Cao,
    • Jarny Choi,
    • Christine A. Wells
    In this article, Wells and colleagues describe an integrated myeloid transcriptome atlas. Analysis resulted in tissue-resident populations being categorized into three broad classes, with culture also found to impact primary cell phenotypes. Pluripotent stem cell–derived cells were compared with their in vivo counterparts, differing in maturation, efferocytosis capacity, and ectopic expression of extracellular matrix genes.