Aug 10, 2021

Volume 16Issue 8p1847-2028
Open Access
Cover Murdaugh et al. (2014–2028) identify histone variant H3.3 regulation by HIRA within a subset of PRC2-targeted chromatin states as a critical determinant of HSC fate upon cell division. The cover image is of a quiescent adult HSC in the bone marrow that retains the potential to differentiate or self-renew by maintaining a poised chromatin state. This image is an abstract acrylic painting by Jacqueline Murdaugh....
Cover Murdaugh et al. (2014–2028) identify histone variant H3.3 regulation by HIRA within a subset of PRC2-targeted chromatin states as a critical determinant of HSC fate upon cell division. The cover image is of a quiescent adult HSC in the bone marrow that retains the potential to differentiate or self-renew by maintaining a poised chromatin state. This image is an abstract acrylic painting by Jacqueline Murdaugh.


  • Inclusivity and diversity: Integrating international perspectives on stem cell challenges and potential

    • Robin Fears,
    • Hidenori Akutsu,
    • Lara Theresa Alentajan-Aleta,
    • Andrés Caicedo,
    • Antonio Carlos Campos de Carvalho,
    • Miodrag Čolić,
    • Jillian Cornish,
    • Giulio Cossu,
    • Patrice Debré,
    • Geoffrey Dierckxsens,
    • Nagwa El-Badri,
    • George Griffin,
    • Patrick Chingo-Ho Hsieh,
    • Maneesha S. Inamdar,
    • Pradeep Kumar,
    • Consuelo Macias Abraham,
    • Romaldas Maciulaitis,
    • Mamun Al Mahtab,
    • Fergal J. O'Brien,
    • Michael Sean Pepper,
    • Volker ter Meulen
    In this article, Fears and colleagues describe an inclusive global initiative by the InterAcademy Partnership examining stem cell opportunities and challenges. Great therapeutic potential brings concerns about the inadequate evidence base used by unregulated clinics. Concerns are also expressed about premature regulatory approval without sufficient evidence. Recommendations cover ethical assessment; pre-clinical and clinical research; regulatory authorization and medicines access; and engagement with patients, policy makers, and the public.



  • Patients' perspectives on the derivation and use of organoids

    • Juli Bollinger,
    • Elizabeth May,
    • Debra Mathews,
    • Mark Donowitz,
    • Jeremy Sugarman
    In this article, Bollinger and colleagues report on in-depth interviews with patients (or their parents) with diseases and conditions where organoid research is advancing scientific understanding and holds clinical translation potential, as well as with general outpatients. These data should inform ethics and policy deliberations.
  • Hypersensitivity response has negligible impact on Hematopoietic Stem Cells

    • Nir Bujanover,
    • Roshina Thapa,
    • Oron Goldstein,
    • Leonid Olender,
    • Omri Sharabi,
    • Michael D. Milsom,
    • Roi Gazit
    In this article, Bujanover and colleagues show that hematopoietic stem cells (HSCs) are not significantly affected by hypersensitivity immune response. This is surprising, as many other viral or bacterial immune stimuli elicit robust activation of HSCs. The lack of activation may suggest a decision mechanism by which HSCs retain quiescence and potency even through an acute hypersensitivity response.
  • A BMP4-p38 MAPK signaling axis controls ISL1 protein stability and activity during cardiogenesis

    • Yanyan Jing,
    • Yonggang Ren,
    • Hagen Roland Witzel,
    • Gergana Dobreva
    In this article, Jing and colleagues describe a key role of BMP4-p38 MAPK signaling in controlling ISL1 protein stability and activity during cardiogenesis through p38-mediated ISL1 phosphorylation at S269. Interfering with p38 MAPK signaling leads to the degradation of ISL1 by the proteasome, resulting in defects in ISL1+ cardiac progenitor cell differentiation and impaired heart morphogenesis and function.


  • Expression dynamics of HAND1/2 in in vitro human cardiomyocyte differentiation

    • Chikako Okubo,
    • Megumi Narita,
    • Azusa Inagaki,
    • Misato Nishikawa,
    • Akitsu Hotta,
    • Shinya Yamanaka,
    • Yoshinori Yoshida
    HAND1 and HAND2 are important cardiac transcriptional factors, but their functions in human cardiogenesis are difficult to analyze. Okubo et al. established HAND1mCherry and HAND2EGFP reporter induced pluripotent stem cells and showed that HAND1 marks cardiovascular progenitors and regulates the gene network of cardiomyocyte proliferation. They further showed that CD105 can be used as a surface marker for proliferative cardiomyocytes.
  • Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology

    • Ranjie Xu,
    • Andrew J. Boreland,
    • Xiaoxi Li,
    • Caroline Erickson,
    • Mengmeng Jin,
    • Colm Atkins,
    • Zhiping P. Pang,
    • Brian P. Daniels,
    • Peng Jiang
    In this article, Jiang and colleagues developed a new brain region-specific, microglia-containing organoid model by co-culturing hPSC-derived primitive neural progenitor cells and primitive macrophage progenitors. In these organoids, appropriate amounts of human microglia integrate into brain organoids at a proper time point, resembling in vivo brain development. Human microglia exhibit phagocytic and synaptic pruning functions and respond to ZIKV infection.
  • Generation of caudal-type serotonin neurons and hindbrain-fate organoids from hPSCs

    • Parvin Valiulahi,
    • Vincencius Vidyawan,
    • Lesly Puspita,
    • Youjin Oh,
    • Virginia Blessy Juwono,
    • Panida Sittipo,
    • Gilgi Friedlander,
    • Dayana Yahalomi,
    • Jong-Woo Sohn,
    • Yun Kyung Lee,
    • Jeong Kyo Yoon,
    • Jae-won Shim
    In this article, Shim and colleagues show that the generation of caudal hindbrain-type 5-HT neurons as well as 5-HT-neuron-enriched hindbrain-like organoids can be achieved through the modulation of SHH and RA signaling in differentiating hPSCs. The authors further propose that these 5-HT neurons in a monolayer and organoid culture system could be utilized as a screening platform for small molecules that trigger the release of 5-HT.
  • The relevance of mitochondrial DNA variants fluctuation during reprogramming and neuronal differentiation of human iPSCs

    • Flavia Palombo,
    • Camille Peron,
    • Leonardo Caporali,
    • Angelo Iannielli,
    • Alessandra Maresca,
    • Ivano Di Meo,
    • Claudio Fiorini,
    • Alice Segnali,
    • Francesca L. Sciacca,
    • Ambra Rizzo,
    • Sonia Levi,
    • Anu Suomalainen,
    • Alessandro Prigione,
    • Vania Broccoli,
    • Valerio Carelli,
    • Valeria Tiranti
    Tiranti and colleagues observed that quality control of iPSCs rarely includes the analysis of mitochondrial DNA (mtDNA), a small circular molecule present in the mitochondria. However, mtDNA variants greatly affect the final phenotype of iPSCs. They highlighted that iPSC-derived neuronal precursors could also present mtDNA variants and underlined the paramount importance of screening mtDNA.
  • Fractalkine signaling regulates oligodendroglial cell genesis from SVZ precursor cells

    • Adrianne E.S. Watson,
    • Monique M.A. de Almeida,
    • Nicole L. Dittmann,
    • Yutong Li,
    • Pouria Torabi,
    • Tim Footz,
    • Gisella Vetere,
    • Danny Galleguillos,
    • Simonetta Sipione,
    • Astrid E. Cardona,
    • Anastassia Voronova
    Watson et al. demonstrate that murine SVZ NPCs and OPCs express Cx3cr1 and bind fractalkine. Exogenous fractalkine increases oligodendrogenesis from SVZ NPCs and OPCs. They also show that OPCs secrete fractalkine and that inhibition of endogenous fractalkine signaling reduces SVZ oligodendrocyte formation. Finally, they show that fractalkine signaling is an important regulator of oligodendrocyte genesis in other brain areas, such as the cerebellum.
  • Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs

    • Jong Bin Choi,
    • Joonsun Lee,
    • Minyong Kang,
    • Bumsoo Kim,
    • Younghee Ju,
    • Hyo-Sang Do,
    • Han-Wook Yoo,
    • Beom Hee Lee,
    • Yong-Mahn Han
    In this article, Han and colleagues suggest new insights into the mechanisms by which mutated HRASG12S induces the bone abnormalities observed in CS patients. Furthermore, they suggest a model in which ECM remodeling proteins (MMP13, TIMP1, and TIMP2) and their related pathways (HRAS-MAPK, TGF-β, and β-catenin) help explain the impaired osteogenesis of CS MSCs.
  • Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma

    • Lorena Lobo de Figueiredo-Pontes,
    • Miroslava K. Adamcova,
    • Srdjan Grusanovic,
    • Maria Kuzmina,
    • Izabela Aparecida Lopes,
    • Amanda Fernandes de Oliveira Costa,
    • Hong Zhang,
    • Hynek Strnad,
    • Sanghoon Lee,
    • Alena Moudra,
    • Anna T. Jonasova,
    • Michal Zidka,
    • Robert S. Welner,
    • Daniel G. Tenen,
    • Meritxell Alberich-Jorda
    The role of natural killer (NK) cells during bone marrow transplantation is not completely understood. Figueiredo-Pontes et al. demonstrate that NK cells impair hematopoietic stem cell (HSC) function via cytokine-mediated mechanisms, and show that NKs depletion from donor cell preparations or neutralizing IFNγ activity improves HSC function and transplantation outcome.
  • The histone H3.3 chaperone HIRA restrains erythroid-biased differentiation of adult hematopoietic stem cells

    • Rebecca L. Murdaugh,
    • Kevin A. Hoegenauer,
    • Ayumi Kitano,
    • Matthew V. Holt,
    • Matthew C. Hill,
    • Xiangguo Shi,
    • Jonathan F. Tiessen,
    • Richard Chapple,
    • Tianyuan Hu,
    • Yu-Jung Tseng,
    • Angelique Lin,
    • James F. Martin,
    • Nicolas L. Young,
    • Daisuke Nakada
    Murdaugh et al. demonstrate that deletion of the histone H3.3 chaperone Hira depletes adult but not fetal liver HSCs by inducing differentiation. Hira regulates H3.3 deposition at a subset of polycomb-repressed chromatin that encodes genes involved in hematopoietic development, which becomes accessible and derepressed in the absence of Hira.