Stem-cell differentiation

  • Article
    | Open Access

    Lineage differentiation and commitment is driven by transcription regulators and chromatin changes. Here the authors report daily profiling of chromatin accessibility and transcriptome changes during human erythropoiesis, relating these changes to lineage potential between erythropoiesis and megakaryopoieis.

    • Grigorios Georgolopoulos
    • , Nikoletta Psatha
    •  & Jeff Vierstra
  • Article
    | Open Access

    To characterize molecular changes during cell type transitions, the authors develop a method to simultaneously measure protein expression and thermal stability changes. They apply this approach to study differences between human pluripotent stem cells, their progenies, parental and allogeneic cells.

    • Pierre Sabatier
    • , Christian M. Beusch
    •  & Roman A. Zubarev
  • Article
    | Open Access

    Mutations in the splicing factor RBM20 cause aggressive Dilated Cardiomyopathy. Here the authors generated RBM20 R636S mutants and knockout in human iPSC-derived cardiomyocytes. Mutant RBM20 showed different target RNA binding, altered splicing and localization to cytoplasmic processing bodies.

    • Aidan M. Fenix
    • , Yuichiro Miyaoka
    •  & Nathan Salomonis
  • Article
    | Open Access

    Polycomb repressive complexes (PRC1 and PRC2) repress genes that are crucial for development via epigenetic modifications; however, their role in differentiation is not well known. Here the authors reveal that a PCGF1-containing PRC1 variant facilitates exit from pluripotency by downregulating target genes and recruiting PRC2.

    • Hiroki Sugishita
    • , Takashi Kondo
    •  & Haruhiko Koseki
  • Article
    | Open Access

    There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.

    • Yonatan R. Lewis-Israeli
    • , Aaron H. Wasserman
    •  & Aitor Aguirre
  • Article
    | Open Access

    Previous approaches to derive embryoids either lack physiological morphology and signaling interactions, or are unconducive to model post-gastrulation development. Here the authors use a high-throughput approach to induce mouse embryonic stem cells into epiblast-like aggregates, which are then co-cultured with mouse trophoblast stem cell aggregates, to yield embryoids with axial morphogenesis and anterior development.

    • Mehmet U. Girgin
    • , Nicolas Broguiere
    •  & Matthias P. Lutolf
  • Article
    | Open Access

    Human and murine embryonic development has disparities, highlighting the need for primate systems. Here, the authors construct a post-implantation transcriptional atlas from non-human primate embryos and show ISL1 controls a gene regulatory network in the amnion required for mesoderm formation.

    • Ran Yang
    • , Alexander Goedel
    •  & Kenneth R. Chien
  • Article
    | Open Access

    Cells in the developing embryo interpret WNT signalling with context-dependence, but the mechanism decoding these cues is unclear. Here, the authors show that combinatorial TALE/HOX activity destabilizes nucleosomes at WNT-responsive regions to activate paraxial mesodermal genes.

    • Luca Mariani
    • , Xiaogang Guo
    •  & Elisabetta Ferretti
  • Article
    | Open Access

    Tendon self-renewal occurs rarely and reconstructive surgery comes with significant limitations. Here the authors present an induced pluripotent stem cell-based method to generate tenocytes, analyze their developmental trajectory using scRNA-seq, and demonstrate their contribution to motor function recovery after Achilles tendon injury via engraftment and paracrine effects.

    • Taiki Nakajima
    • , Akihiro Nakahata
    •  & Makoto Ikeya
  • Article
    | Open Access

    The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.

    • Jun Jie Tan
    • , Jacques P. Guyette
    •  & Harald C. Ott
  • Article
    | Open Access

    Differentiation of hPSCs to cardiomyocytes suffers from high variability. Here the authors report a label-free live cell imaging platform based on autofluorescence imaging to enable the prediction of cardiomyocyte differentiation efficiency from hPSCs.

    • Tongcheng Qian
    • , Tiffany M. Heaster
    •  & Melissa C. Skala
  • Article
    | Open Access

    The transcriptional regulators underlying the induction and differentiation of dense connective tissues remain largely unknown. Here the authors generate tendon and fibrocartilage cells from mouse embryonic stem cells and apply scRNA-seq to identify molecular regulation of the cell fate switch between these lineages.

    • Deepak A. Kaji
    • , Angela M. Montero
    •  & Alice H. Huang
  • Article
    | Open Access

    Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERRγ agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.

    • Kenji Miki
    • , Kohei Deguchi
    •  & Yoshinori Yoshida
  • Article
    | Open Access

    Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.

    • Blaise Su Jun Low
    • , Chang Siang Lim
    •  & Adrian Kee Keong Teo
  • Article
    | Open Access

    From single-cell transcriptome analyses to defining culture media for spheroids, the authors provide a census of information to understand the development of human pancreatic progenitors. This approach identifies signalling pathways (EGF and FGF) regulating progenitor proliferation.

    • Carla A. Gonçalves
    • , Michael Larsen
    •  & Anne Grapin-Botton
  • Article
    | Open Access

    G-quadruplexes (G4) can be formed from DNA sequences containing consecutive guanines organized in 4-interspaced tandem repeats. Here the authors reveal the association between G4 structures present at specific loci in Alzheimer’s disease neurons and reduced gene expression and perturbed alternative splicing.

    • Roy Hanna
    • , Anthony Flamier
    •  & Gilbert Bernier
  • Article
    | Open Access

    During Plasmodium intra-erythrocytic developmental, parasites compromise the structural integrity of host red-blood cells. Here, Clark et al. develop a flow cytometric osmotic stability assay to show that P. vivax infection destabilizes host reticulocytes, which are less stable than P. falciparum-infected normocytes.

    • Martha A. Clark
    • , Usheer Kanjee
    •  & Manoj T. Duraisingh
  • Article
    | Open Access

    Cardiomyocyte maturation and the acquisition of phenotypes is poorly understood at the single cell level. Here, the authors analyse the transcriptome of single cells from neonatal to adult heart and reveal that peroxisome proliferator-activated receptor coactivator-1 mediates the phenotypic shift.

    • Sean A. Murphy
    • , Matthew Miyamoto
    •  & Chulan Kwon
  • Article
    | Open Access

    The role of RNA polymerase II (Pol II) recruitment during adult stem cell differentiation is well understood, but not that of Pol II elongation. Here, the authors show that 30% of epidermal stem cell differentiation genes depend on SPT6 and PAF1 for Pol II elongation, and SPT6 loss leads to an intestine-like phenotype.

    • Jingting Li
    • , Xiaojun Xu
    •  & George L. Sen
  • Article
    | Open Access

    Tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, the authors describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the MINPP1 gene, characterised by intracellular imbalance of inositol polyphosphate metabolism.

    • Ekin Ucuncu
    • , Karthyayani Rajamani
    •  & Vincent Cantagrel
  • Article
    | Open Access

    Neuronal differentiation requires rearrangement of the transcriptional and chromatin landscapes of neural cells. Here, the authors study in-vitro neuronal differentiation of murine embryonic stem cells (ESCs) to show that this process is modulated by DOT1L activity, which regulates H3K79me2 accumulation, and preserves accessibility of SOX2-bound enhancers.

    • Francesco Ferrari
    • , Laura Arrigoni
    •  & Thomas Manke
  • Article
    | Open Access

    The fetal murine foregut develops into visceral organs via interactions between the mesoderm and endoderm, but how is unclear. Here, the authors use single cell RNAseq to show a diversity in organ specific splanchnic mesoderm cell-types, infer a signalling network governing organogenesis and use this to differentiate human pluripotent stem cells.

    • Lu Han
    • , Praneet Chaturvedi
    •  & Aaron M. Zorn
  • Article
    | Open Access

    Induced pluripotent stem cell (iPSC) derived dopaminergic neurons are a promising source for cell-based Parkinson’s disease (PD) therapy. Here the authors report a comprehensive pre-clinical evaluation of the safety and efficacy of dopaminergic progenitors derived from a clinical-grade human iPSC line.

    • Daisuke Doi
    • , Hiroaki Magotani
    •  & Jun Takahashi
  • Article
    | Open Access

    ADNP has been connected to neural developmental disorders. Here, the authors uncover a role for ADNP in neural induction and differentiation via β-Catenin stabilization, with ADNP disruption in zebrafish leading to defective neurogenesis and decreased Wnt signaling.

    • Xiaoyun Sun
    • , Xixia Peng
    •  & Yuhua Sun
  • Article
    | Open Access

    Chronic lung diseases are characterized by molecular and cellular composition changes. Here the authors use single-cell RNA sequencing to map cell type-specific changes in human tracheal epithelium related to smoking, and to provide evidence for a tuft-like progenitor for pulmonary neuroendocrine cells and ionocytes.

    • Katherine C. Goldfarbmuren
    • , Nathan D. Jackson
    •  & Max A. Seibold
  • Article
    | Open Access

    Deriving functional pancreatic cell types from human stem cells may have important clinical applications. Building on previous work, here the authors generate stem cell-derived alpha cells via a polyhormonal intermediate, which have a gene expression pattern similar to human islet alpha cells and behave as such when transplanted into mice.

    • Quinn P. Peterson
    • , Adrian Veres
    •  & Douglas A. Melton
  • Article
    | Open Access

    Classical human dendritic cells (cDCs) are rare sentinel cells specialized in regulating adaptive immunity. Here, the authors show that expression of membrane bound FLT3L, along with stem cell factor (SCF) and CXCL12 in stromal cells induces specification of pre/AS-DCs, type 1 and type2 cDC from haematopoietic stem cells.

    • Giorgio Anselmi
    • , Kristine Vaivode
    •  & Pierre Guermonprez
  • Article
    | Open Access

    To model hepatocyte function accurately in vitro, it is necessary to generate and maintain a polarized epithelium. Here, the authors describe a protocol to generate polarized human pluripotent stem cell-derived hepatocyte-like cells (HLCs) to model enteric virus production and drug secretion in vitro.

    • Viet Loan Dao Thi
    • , Xianfang Wu
    •  & Charles M. Rice
  • Article
    | Open Access

    Hepatocytes grown in a dish are immature and do not metabolize compounds as a real liver would. Here, the authors supply stem cell-derived hepatocytes with amino acids at a higher concentration than nutritionally necessary, changing the metabolism of these cells, making them more mature and useful for drug screening and toxicity studies.

    • Ruben Boon
    • , Manoj Kumar
    •  & Catherine M. Verfaillie
  • Article
    | Open Access

    The identity of the earliest murine in vivo lung epithelial progenitors (marked by NKX2-1 expression) is unclear. Here, the authors use single-cell RNA sequencing to define the genetic program of these lung primordial progenitors, which will improve in vitro lung specification of pluripotent stem cells.

    • Laertis Ikonomou
    • , Michael J. Herriges
    •  & Darrell N. Kotton
  • Article
    | Open Access

    Neurogenesis is an ordered transition from pluriptotent cells to neural precursor cells (NPCs) to neurons. Here the authors show that loss of the lysine demethylases JMJD3 and UTX leads reduced DNA accessibility at neurogenesis loci in human NPCs, and that the chromatin remodeller BAF can rescue differentiation defects.

    • Yongli Shan
    • , Yanqi Zhang
    •  & Guangjin Pan
  • Article
    | Open Access

    Human induced pluripotent stem cell-derived intestinal organoids (HIOs) are powerful tools to study development and diseases of the gastrointestinal tract. Here, the authors develop a directed differentiation protocol to generate mesenchyme-free HIOs that can be patterned towards proximal small intestine or colonic epithelium, and demonstrated their utility in modeling CFTR function.

    • Aditya Mithal
    • , Amalia Capilla
    •  & Gustavo Mostoslavsky
  • Article
    | Open Access

    Acetylcholine regulates intestinal epithelial secretion via muscarinic Gq-coupled receptors but its role in cell differentiation is unclear. Here, the authors show that Prox1-positive endocrine cells are sensors for the cholinergic intestinal niche and can trigger increased differentiation of enteroendocrine DCLK1-positive tuft cells.

    • Moritz Middelhoff
    • , Henrik Nienhüser
    •  & Timothy C. Wang
  • Article
    | Open Access

    How reproducible human kidney organoids derived from different iPSC lines are, and how faithful they are to human kidney tissue remain unclear. Here, the authors use four human iPSC lines to derive kidney organoids and show how organoid composition is reproducible, comparable to human tissue and of improved quality after transplantation.

    • Ayshwarya Subramanian
    • , Eriene-Heidi Sidhom
    •  & Anna Greka
  • Article
    | Open Access

    Trophectoderm lineage development is essential for implantation, placentation, and healthy pregnancy. Here the authors map super-enhancers (SEs) in trophoblast stem cells and find both TE-specific master regulators and 150 previous uncharacterised transcription factors that are SE-associated, providing insight into trophectoderm-specific regulatory networks.

    • Bum-Kyu Lee
    • , Yu jin Jang
    •  & Jonghwan Kim
  • Article
    | Open Access

    Barriers underlying the inefficiency of reprogramming cells to pluripotency are poorly defined. Here the authors identify a transient interval soon after pluripotency exit that permits high-efficiency reprogramming and is facilitated by OCT4 bound elements displaying unique silencing behaviour during differentiation.

    • Sudhir Thakurela
    • , Camille Sindhu
    •  & Alexander Meissner
  • Article
    | Open Access

    Notch signaling mediates intestinal enteroblast specification in Drosophila but the molecular mechanism as to how this is regulated is unclear. Here, the authors show that the transcription factor Klumpfuss ensures enteroblast commitment through repression of enteroendocrine cell fate downstream of Notch.

    • Jerome Korzelius
    • , Sina Azami
    •  & Heinrich Jasper
  • Article
    | Open Access

    Organoid technology has been applied to model many types of organs in vitro, although structures containing multiple germ layers, such as limb buds, have not been generated. Here, the authors induce limb bud-like tissues from mouse ESCs that can be functionally integrated after transplantation.

    • Shunsuke Mori
    • , Eriko Sakakura
    •  & Mototsugu Eiraku
  • Article
    | Open Access

    Mouse incisor growth depends upon mesenchymal stromal cells (MSCs) and transit amplifying cells (TACs). Here the authors describe a distinct population of MSCs that is maintained by TACs through Dlk1 ligand and that contribute to MTACs and mesenchymal lineages including dental pulp and odontoblasts.

    • Jemma Victoria Walker
    • , Heng Zhuang
    •  & Bing Hu
  • Article
    | Open Access

    In neonatal testes, prospermatogonia generate both spermatogonia for the first wave of spermatogenesis and spermatogonial stem cells (SSCs) for maintenance of spermatogenesis in males. Here the authors characterize the development of mouse SSCs from prospermatogonia using single-cell RNA-seq and transplantation assays.

    • Nathan C. Law
    • , Melissa J. Oatley
    •  & Jon M. Oatley
  • Article
    | Open Access

    Human Hematopoietic stem and progenitor cells (HSPCs) are commonly defined by CD34 expression. Here, the authors map single-cell RNA states both inside and outside the CD34 compartment, uncovering previously unappreciated branchpoints and validating CD164 as an efficient marker for early HSPCs.

    • Danilo Pellin
    • , Mariana Loperfido
    •  & Luca Biasco
  • Article
    | Open Access

    Chromatin looping allows for enhancer–promoter interactions that regulate transcription. Here the authors show that activation of embryonic myogenesis is associated with establishment of long-range chromatin interactions centred on Pax3-bound loci and find that Ldb1 functions as the mediator of looping interactions at a subset of Pax3 binding sites.

    • Alessandro Magli
    • , June Baik
    •  & Rita C. R. Perlingeiro
  • Article
    | Open Access

    Human induced pluripotent stem cells (hiPSCs) generate all cell types in the body, but different lines can differ in their potential. Here, the authors determine that higher endogenous levels of SALL3 in hiPSCs lead to ectoderm differentiation bias and reduced mesoderm/endoderm due to DNMT3B mediated DNA methylation.

    • Takuya Kuroda
    • , Satoshi Yasuda
    •  & Yoji Sato