Series on Stem Cell Biology

Stem cell biology has emerged as one of the most exciting areas of basic and biomedical research. This month, we launch a series of specially commissioned articles that discuss recent advances and challenges in this field.

Yaffe and colleagues discuss the issues surrounding the authentication and quality of induced pluripotent stem cells.

Barker and colleagues review the history and recent developments of organoid cultures derived from pluripotent stem cells and adult epithelia, and discuss how the technology can be used for basic research as well as translational applications.

Passegué and colleagues discuss recent advances in our understanding of the metabolic control of stem cell function, and how stem cell metabolism relates to homeostasis and ageing.

De novo generation of haematopoietic stem cells from different human pluripotent stem cell sources remains a high priority for haematology and regenerative medicine. At present, efficient derivation of functional haematopoietic stem cells with the capability for definitive in vivo engraftment and multi-lineage potential remains challenging. Here, we discuss recent progress and strategies to overcome obstacles that have thwarted past efforts. In addition, we review promising advances in the generation of mature blood lineages and the potential of induced pluripotent stem cells.

Visvader and Clevers discuss how stem cells from different tissues, such as the intestine, mammary gland and skeletal muscle, follow different strategies and hierarchies to maintain their complex, tissue-specific balance.

Nerlov and colleagues show that expression of mKitL by cortical vascular endothelial cells is important for DN1 progenitor maintenance, whereas expression of mKitL by cortical thymic epithelial cells is required for maintaining DN2 progenitor cells.

Nowell et al. report that chronic inflammation of the corneal epithelium activates β-catenin signalling through YAP/TAZ-dependent mechanotransduction, leading to epidermal differentiation on the ocular surface and corneal squamous cell metaplasia.

Lacaud and colleagues show that the GFI1 transcriptional repressors are required for endothelial-to-haematopoietic transition in the aorta–gonad–mesonephros region of the mouse embryo by inhibiting the endothelial gene expression program via LSD1.

By comparing the metabolomes, transcriptomes and epigenomes of human pluripotent stem cell lines, Sperber et al. show that interplay between the metabolome and histone modifications drives the metabolic switch from naive to primed pluripotency.

Drosophila intestinal stem cells (ISCs) respond to changes in diet, particularly L-glutamate levels, by modulating Ca²⁺ signalling to adapt their proliferation rate; furthermore, Ca²⁺ is shown to be central to the response of ISCs to a wide range of dietary and stress stimuli.

RNA interference screens were used to identify chromatin-associated factors that impede reprogramming of somatic cells into iPS cells; suppression of the chromatin assembly factor CAF-1 enhances the generation of iPS cells by rendering chromatin more accessible to pluripotency transcription factors.

Innate lymphoid cells increase the growth of mouse intestinal organoids via IL-22 production; recombinant IL-22 promotes growth of both mouse and human organoids, and promotes mouse intestinal stem cell (ISC) expansion and ISC-driven organoid growth via a STAT3-dependent pathway and independently of Paneth cells; IL-22 treatment in vivo enhances the recovery of ISCs from intestinal injury.

Dystrophin is expressed in muscle stem cells, in which it regulates their cell division and proper repopulation.

Ding and colleagues show that somatic cell reprogramming does not depend on Atg5-dependent canonical autophagy, but requires mitochondrial clearance in an Atg5-independent manner downstream of AMPK.

Human pluripotent stem cells can be differentiated into exocrine pancreas progenitor organoids, allowing studies of development and pancreatic cancer modeling.

Human induced pluripotent stem cells show no consistent differences from human embryonic stem cells in a study that controls for several sources of variability.

Using single-cell profiling of Nanog and Oct4 protein levels in mouse embryonic stem cells, Schroeder and colleagues show that differences in Nanog levels are not correlated with differences in expression of other pluripotency factors and cell fate.

The kidney arises from two types of progenitors; here, the signalling conditions that induce the production of collecting ducts and functional nephrons from human pluripotent stem cells are determined, and organoids that recapitulate the functional regionalization of the kidney are produced.

Human pluripotent stem cells are differentiated into renal vesicles that spontaneously form kidney organoids.

Patel et al. report that Drosophila intestinal stem cell tumours are generated by stress- and EGFR-signalling, followed by extrusion of neighbouring enterocytes, enterocytic cytokine expression and paracrine signalling for tumour growth.

By analysing inducible knockout mice, Scherer and colleagues report that the adipogenic transcription factor C/EBPα is dispensable for white adipogenesis in mouse embryos, but not in adults.

PIK3CA mutations are associated with distinct types of human breast cancers but the cellular origin and mechanisms responsible for this heterogeneity were unclear; here, using a genetic approach in mice, PIK3CA mutations are shown to activate a genetic program directing multiple cell fates in normally lineage-restricted cell types.

PIK3CA mutations are associated with distinct types of human breast cancers but the cellular origin and mechanisms responsible for this heterogeneity were unclear; here, using a genetic approach in mice, the PIK3CA^H1047R mutation is shown to induce multipotent stem-like cells and mammary tumours with different levels of malignancy depending on the cell of origin.

The development of human cardiovascular progenitor cells provides a renewable source of cardiac cell types.

Forbes and colleagues report on a population of hepatic progenitor cells that regenerate the adult liver in a mouse model where more than 98% of all hepatocytes are irreversibly damaged.

Noguchi and colleagues report the generation of stomach-like tissue from mouse embryonic stem cells. They show that the tissue contains all stomach-specific cell types and secretes acid and digestive enzyme.

Cowan and colleagues report a method to generate mature endothelial or vascular smooth muscle cells from human pluripotent stem cells with high efficiency and purity.

Lopez-Otin and colleagues report that NF-κB signalling hyperactivation in progeria syndrome fibroblasts inhibits their reprogramming into iPS cells. Blockade of this pathway or the downstream factor DOTL1 rescues senescence-related phenotypes.

Preconditioning the niche after lung injury allows better engraftment by fetal lung tissue and repair.

Lineage tracing shows that, contrary to a recent report, c-kit⁺ cells take on a vascular endothelial cell fate, not an epithelial one, after lung injury or during normal homeostasis.

Mutations in mitochondrial (mt)DNA are associated with severe disorders for which treatment is currently limited; this study shows that mtDNA mutations can be genetically corrected and normal metabolic function restored in cells derived from patients with mtDNA disease and reprogrammed to pluripotency through factor-mediated reprogramming or via a somatic cell nuclear transfer approach.

In the uninjured liver, a population of self-renewing, diploid hepatocytes is identified near the central vein; these cells respond to Wnt signals that are provided by the adjacent central vein endothelial cells, and can give rise to all other hepatocytes to maintain liver homeostasis.

Pei and colleagues report that the oncogene c-Jun acts as a somatic cell reprogramming barrier, and that its truncated dominant-negative form can substitute for Oct4 in reprogramming.

Methods for direct conversion of fibroblasts to other cell types using pluripotency-associated factors generate a transient pluripotent state.

Methods for direct conversion of fibroblasts to other cell types using pluripotency-associated factors generate a transient pluripotent state.

Qin, Pei and colleagues report that autophagy is induced early during somatic cell reprogramming into induced pluripotent stem cells. mTORC1 and autophagy control reprogramming efficiency by modulating mitochondrial architecture and p62 levels.

Jasper and colleagues report that following intestinal damage in Drosophila, haemocytes recruited to the intestine secrete Dpp, promoting intestinal stem cell proliferation and, at later stages of regeneration, the re-establishment of intestinal stem cell quiescence.

Mouse hair follicles in the skin cycle between growth and regression, while maintaining a pool of stem cells for continued regeneration; here, live imaging is used to show that a combination of niche-induced stem cell apoptosis and epithelial phagocytosis underlies regression, regulating the stem cell pool.

Zhang and colleagues show that the ITIM-containing receptor LAIR1 supports self-renewal and survival of acute myeloid leukaemia stem cells through a signalling pathway that includes the SHP-1 phosphatase, CAMK1 kinase and CREB transcription factor.

Mostoslavsky and colleagues reveal that in embryonic stem cells (ESC) the deacetylase SIRT6 regulates pluripotency genes, which in turn controls ESC differentiation though the activity of Tet enzymes.

Keller and colleagues show that haemogenic and vascular endothelium represent distinct lineages and that haemogenic endothelium gives rise to multipotent haematopoietic progenitors through a NOTCH-dependent endothelial-to-haematopoietic transition.

By deciphering the transcriptional network of human embryonic pancreatic progenitors, Ferrer and colleagues identify the Hippo-responsive transcription factor TEAD1 as a regulator of the pancreatic progenitor enhancer programme.

Tzahor and colleagues show that ErbB2 signalling is required for cardiomyocyte proliferation in fetal and postnatal mouse hearts, and that its activation in adult hearts promotes cardiomyocyte proliferation and regeneration following myocardial ischaemic injury.

Visvader and colleagues report that in the mouse mammary gland, EGF and mTOR signalling induce expression of the anti-apoptotic Bcl2 family member Mcl-1 and show that this is required for the survival of milk-producing mammary epithelial cells.

Rodeheffer and colleagues show that a high-fat diet in mice activates Akt2 signalling in adipocyte precursors within white adipose tissue deposits, leading to their proliferation and differentiation into adipocytes, and to obesity.

Chai and colleagues report that Gli1-expressing cells within the mouse cranial suture mesenchyme contribute to all cranial bones, and their ablation leads to impaired skull injury repair, skull growth arrest and osteoporosis.

Khokha and colleagues report that lack of the metalloproteinase inhibitors TIMP1 and TIMP3 in female mice increases the size of the mammary basal stem cell pool and that this is maintained in ageing mice.

Magness and colleagues present a microwell-based culture system to analyse interactions between intestinal stem cells (ISCs) and Paneth cells, and show that their direct contact enhances formation of ISC-derived organoids.

Bao and colleagues report that glioblastoma cancer stem cells produce periostin, which in turn recruits tumour-associated macrophages to the tumour site to foster growth.

Ding and colleagues report that blood platelets recruited to the lung by injury release the chemokine SDF-1, which interacts with its receptor CXCR4 on pulmonary capillary endothelial cells and thereby initiates alveolar regeneration.

Imajo and colleagues report that the Hippo signalling pathway components YAP and TAZ act via TEAD to promote intestinal stem/progenitor cell proliferation and via Klf4 to trigger their differentiation.

Loss of muscle satellite cells during aging has been thought to contribute to sarcopenia, but experimentally induced depletion of these cells in adult mice does not result in this condition.

Generation of functional T-cells for therapeutic purposes requires a thymic epithelium. Blackburn and colleagues show that FOXN1 expression in fibroblasts triggers the formation of functional thymic epithelial cells that support T-cell differentiation from haematopoietic progenitors.

This study uses single-cell expression profiling of pluripotent stem cells after various perturbations, and uncovers a high degree of variability that can be inherited through cell divisions—modulating microRNA or external signalling pathways induces a ground state with reduced gene expression heterogeneity and a distinct chromatin profile.

The in vitro generation, from pluripotent stem cells, of three-dimensional human gastric organoids (hGOs) that contain a physiological gastric epithelium comprising both progenitor and differentiated cell types, and have expected functional characteristics is described, as is modelling the pathophysiological response of the human stomach to Helicobacter pylori using these hGOs.

This study describes the conversion of human fetal and adult vascular endothelial cells into engraftable haematopoietic progenitors by transduction with some transcription factors and then culture on a vascular niche feeder layer; the haematopoietic progenitors may be useful for the generation of engraftable healthy and long-lasting haematopoietic cells for treatment of inherited and acquired blood disorders.