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Stem cells from development to the clinic

Recent advances in our understanding of stem cell differentiation and fate determination have enabled us to use stem cells in vitro and in vivo in a variety of applications, such as disease modelling, drug screening and for transplantations. This Collection of primary research articles, reviews and protocols from across the Nature journals involves both basic and translational research.

Research articles presented here highlight important work on stem cell differentiation, pluripotency states, lineage specification, development, genetic & epigenetic changes and metabolic regulation. They further explore how this knowledge can be applied to develop stem cell technologies that allow more detailed study of the onset of neural, intestinal, liver, lung, cardiac, muscle and blood diseases, as well as cancer. We showcase papers on the use of stem cells in the clinic to treat a genetic skin disorder and macular degeneration. In addition, the collection includes a number of peer-reviewed protocols from Nature Protocols that focus on iPSC reprogramming and the generation of organoids. Opinion and Review articles discuss the advances in this field, ethical implications of the work, as well as challenges faced by the scientific community as researchers attempt to apply the knowledge gained from basic studies in the clinic. 

Disease modelling & Regeneration

Organoids are 3D structures derived from stem cells that recapitulate some key characteristics of real organs. The authors review recent progress in organoid derivation and applications and outline how advances in other disciplines might lead to more physiologically relevant organoids.

Review Article | | Nature Reviews Genetics

Human pluripotent stem cells were used to develop dorsal and ventral forebrain 3D spheroids, which can be assembled to study interneuron migration and to derive a functionally integrated forebrain system with cortical interneurons and glutamatergic neurons.

Article | | Nature

This Review discusses how stem cell bioengineering can advance regenerative medicine by giving insight into the design principles that underlie different levels of stem cell systems — from the inner circuitry in single cells and the stem cell niche to systemic interactions between organs and tissues.

Review Article | | Nature Reviews Genetics

The Huntington's disease (HD) induced pluripotent stem cell (iPSC) consortium describe the combined use of differentiated patient-derived iPSCs and systems biology to discover underlying mechanisms in HD. They identify neurodevelopmental deficits in HD cells that can be corrected in cells and in vivo with a small molecule.

Article | | Nature Neuroscience

Wound healing is essential to repair the skin after injury and distinct stem cells in the epidermis are known to contribute to the process. Here the authors perform molecular, functional and clonal analysis and reveal the individual contribution of stem cells coming from different epidermal compartments to the wound-healing process in mice.

Article | open | | Nature Communications

Endocrine (such as diabetes) and exocrine (such as pancreatitis) disorders of the pancreas have a substantial burden worldwide. This Review explores the potential of regenerative medicine and cell-based approaches to restore both endocrine and exocrine pancreatic function, describing insights into cell replacement, implantation and reprogramming.

Review Article | | Nature Reviews Gastroenterology & Hepatology

The conflicting results of cell therapy clinical trials for heart regeneration have led to some confusion over the efficacy of this approach. This Review summarizes the main outcomes of these studies and gives perspectives for future cell-based regenerative trials largely based on the primary therapeutic target: regeneration of lost myocardium by exogenous cells or promotion of intrinsic repair though paracrine signalling.

Review Article | | Nature Reviews Cardiology

Human induced pluripotent stem cells (hiPSCs) can be differentiated into many cardiovascular cell types, including cardiomyocytes and endothelial cells. hiPSC-derived cardiovascular cells can recapitulate patient-specific and disease-specific phenotypes. In this Review, Chen et al. discuss how hiPSCs can be used as a platform for cardiovascular drug development and disease modelling, and can facilitate individualized therapy in the era of precision medicine.

Review Article | | Nature Reviews Cardiology

In this Review, Drost and Clevers discuss the recent advances in organoid models of cancer and how they can be exploited to drive the translation of basic cancer research into novel patient-specific treatment regimens in the clinic.

Review Article | | Nature Reviews Cancer

Volumetric muscle loss leads to functional muscle impairment, and current stem cell-based treatments show limited efficacy. Here, the authors generate a stem cell scaffold, implant it in mice, and show that an exercise regimen enhances innervation and restoration of muscle function in mice.

Article | open | | Nature Communications

Adult muscles contain quiescent stem cells, known as satellite cells, which are activated upon injury, enabling muscle repair and replenishment of the stem cell pool. Recent studies have shed light on the molecular circuitry regulating satellite cell fate decision and the impairment of this circuitry during degenerative muscle diseases and ageing.

Review Article | | Nature Reviews Molecular Cell Biology

Advances in the derivation of pluripotent stem cells (PSCs) and their differentiation to specific cell types could have diverse clinical applications. Trounson and DeWitt provide an overview of the progress in using embryonic stem cell and induced PSC derivatives for disease treatment and discuss the potential and limitations of such approaches.

Science and Society | | Nature Reviews Molecular Cell Biology

The use of cultured human pluripotent stem cells (PSCs) to model human diseases has revolutionized the ways in which we study monogenic, multigenic and epigenetic disorders, by overcoming some of the limitations of animal models. PSC-based disease models are generated using various strategies and can be used for the discovery of new drugs and therapies.

Review Article | | Nature Reviews Molecular Cell Biology

Macrophages, a type of white blood cell, when derived from embryonic stem cells in the laboratory reduce fibrosis in chronic liver disease. Lesley Forrester and colleagues from the University of Edinburgh found murine embryonic stem-cell-derived macrophages (ESDM) were morphologically similar to bone marrow-derived macrophages (BMDM), previously found to reduce fibrosis and improve liver function in mice with induced liver injury. Using a novel technique, the team found ESDM engulfed fewer particles at a slower rate than BMDM, indicating ESDM were less inflammatory. A higher dose of ESDM was required to have the same effect of BMDM to help liver fibrosis regression. However, they were more efficient in repopulating mouse livers depleted of liver-specific macrophages and also significantly improved liver function, indicating ESDM were similar to resident macrophages in the liver and had therapeutic potential.

Article | open | | npj Regenerative Medicine

Adult stem cells

On the basis of transplantation experiments it is generally believed that a very small number of haematopoietic stem cells maintain multi-lineage haematopoiesis by stably producing a hierarchy of short-lived progenitor cells; here a new transposon-based labelling technique shows that this might not be the case during non-transplant haematopoiesis, but rather that a large number of long-lived progenitors are the main drivers of steady-state haematopoiesis during most of adulthood.

Article | | Nature

Lineage-tracing experiments in the mouse show that Lgr6, but not Lgr5, functions as a cancer stem marker in skin squamous cell carcinomas (SCCs). The authors also show that Lgr6-knockout mice are predisposed to SCC development, through a mechanism that includes compensatory upregulation of Lgr5.

Article | | Nature Genetics

Michael Kharas and colleagues characterize the MSI2 protein interactome in leukemia cells and subsequently perform a functional screen identifying 24 genes required for leukemia in vivo. They focus on the RNA-binding protein SYNCRIP, showing that it regulates Hoxa9 and other transcripts involved in a myeloid leukemia stem cell program.

Article | | Nature Genetics

Applying a new, more sensitive single-cell transcriptomics method to diagnosis, remission and progression samples from patients with chronic myeloid leukemia reveals insight into the heterogeneity of cells that resist treatment with targeted therapy, as well as into the dynamics of disease progression and its effects on nontransformed hematopoietic stem cells.

Article | | Nature Medicine

Microenvironmental pressures in glioblastoma select for glioma stem cells (GSCs) subpopulations that are maintained through preferential activation of BMI1 and EZH2 in different niches. Given the high degree of intratumor heterogeneity, combined pharmacological inhibition of Polycomb repressive complexes targets proneural and mesenchynmal GSCs and expands lifespan in mice, warranting the therapeutic evaluation of this approach in patients with glioblastoma.

Article | | Nature Medicine

Decline in stem cell function causes loss of tissue homeostasis and increased incidence of age-related diseases. During ageing, adult stem cells accumulate damage and the niche in which they reside malfunctions. These defects are associated with changes in the epigenome that contribute to organ dysfunction and disease.

Review Article | | Nature Reviews Molecular Cell Biology

Some terminally differentiated cells have the capacity to de-differentiate or transdifferentiate under physiological conditions as part of a normal response to injury. Recent insights have been gained into the role of this cell plasticity in maintaining tissue and organ homeostasis, and this has important implications for cell-based therapies.

Review Article | | Nature Reviews Molecular Cell Biology

A select group of bone marrow cells (BMCs) with the capacity to regenerate the heart are not all the same. Working with mouse cells, a team led by Annarosa Leri used single cell-based analytical techniques to test whether all BMCs that express a cell surface marker called c-kit possess the ability to form new heart tissue. They found that these BMCs, despite their shared expression of c-kit, were not a uniform population. Only a subset could give rise to various cell lineages in the heart. Others remained in an undifferentiated state and retained their bone marrow identity, even within the damaged heart. The findings could help explain why researchers have reported such disparate results in the past when assessing the heart repairing potential of c-kit-positive BMCs.

Article | open | | npj Regenerative Medicine

Co-culture of meniscal cartilage-forming cells with fat-derived stem cells can lead to enhanced cartilage matrix production when cultured under simulated microgravity. Adetola Adesida from the University of Alberta in Edmonton, Canada, and colleagues cultured two types of cells found together in the knee—cartilage-forming chondrocyte cells (taken from the meniscus) and mesenchymal stem cells (isolated from the infrapatellar fat pad)—in a rotary cell culture system designed to model weightlessness on Earth. Simulated microgravity enhanced the synergistic interaction between the two types of cells in culture, resulting in more matrix production, but it also prompted the cartilage-forming cells to differentiate towards bone-forming cells, as evidenced by gene expression analysis. These findings suggest that microgravity and simulated microgravity-based culture technologies could help bioengineers grow knee replacements for people with meniscus tears, but increased bone-directed differentiation could pose a possible problem for astronauts on prolonged missions.

Article | open | | npj Microgravity

Signals from a protein that regulates cell division are essential to maintain the stem cells that regenerate hair follicles. Jeff Biernaskie and colleagues at Canada’s University of Calgary found signals from platelet-derived growth factor (PDGF) promote self-renewal of ‘hair follicle dermal stem cells’ (hfDSCs)—cells present at the bottom of hair follicles important for their regeneration. They ‘turned off’ the gene responsible for PDGF production in hfDSCs in mice. This led to a significant reduction in the stem cells with successive hair cycles. They also tested the effects of PDGF signaling molecules on isolated hfDSCs and found they improved their ability to proliferate and to induce follicle regeneration. The results suggest disruption to PDGF signaling may contribute to hair loss. PDGF could be an important additive to rapidly expand hfDSCs ex vivo for cell-based therapies.

Article | open | | npj Regenerative Medicine

Reprogramming & Pluripotency

The authors surveyed whole-exome and RNA-sequencing data from 252 unique pluripotent stem cell lines, some of which are in the pipeline for clinical use, and found that approximately 5% of cell lines had acquired mutations in the TP53 gene that allow mutant cells to rapidly outcompete non-mutant cells, but do not prevent differentiation.

Letter | | Nature

A screen in which combinatorial pairs of transcription factors are exogenously expressed in fibroblasts identifies different combinations that reprogram these cells into induced neuronal cells with diverse functional properties.

Article | | Nature

The authors analyze time-resolved changes in genome topology, gene expression, transcription-factor binding, and chromatin state during iPSC generation. They conclude that 3D genome reorganization generally precedes gene expression changes and that removal of locus-specific topological barriers explains why pluripotency genes are activated sequentially during reprogramming.

Article | | Nature Genetics

Ernesto Guccione and colleagues report that the transcription factor PRDM15 regulates naive pluripotency in mouse embryos and embryonic stem cells and in derivation of mouse and human iPSCs. They further show that PRDM15 promotes WNT signaling and inhibits MAPK–ERK signaling by directly regulating the expression of R-spondin1 and Sprouty1, respectively.

Article | | Nature Genetics

This study identifies regulatory variants in sensory neurons derived from induced pluripotent stem cells. Despite differentiation-induced variability, an allele-specific method allowed detection of loci influencing gene expression, chromatin accessibility and RNA splicing.

Article | | Nature Genetics

Pandya et al. describe a protocol to differentiate human and mouse iPSCs into cells with the phenotype, transcriptional profile and functional properties of microglia. The treatment of murine intracranial malignant gliomas with these cells demonstrates their potential clinical use. These microglia-like cells will enable further studies into the role of microglia in health and disease.

Technical Report | | Nature Neuroscience

In this article, the authors review the mechanisms by which the pluripotency gene regulatory network governs the acquisition, maintenance and dissolution of the pluripotent state, including the interaction of these networks with chromatin-mediated and RNA-mediated regulatory mechanisms. They discuss recent evidence for alternative pluripotency states and the factors that affect transitions between these states.

Review Article | | Nature Reviews Genetics

The ectopic expression of a defined set of transcription factors can experimentally reprogramme somatic cells into other cell types, including pluripotent cells. This method enables exploration of the molecular characteristics of pluripotency, cell specification, differentiation and cell fate stability, as well as their transcriptional and epigenetic regulation.

Review Article | | Nature Reviews Molecular Cell Biology

This year marks the tenth anniversary of the generation of induced pluripotent stem cells (iPSCs) by transcription factor-mediated somatic cell reprogramming. Takahashi and Yamanaka portray the path towards this ground-breaking discovery and discuss how, since then, research has focused on understanding the mechanisms underlying iPSC generation and on translating such advances to the clinic.

Timeline | | Nature Reviews Molecular Cell Biology

Regulation of pluripotency: Li and Belmonte review the pluripotency gene regulatory network, the molecular principles of pluripotency gene function, regulation by RNA-binding proteins and alternative splicing, heterogeneity and alternative pluripotency states.

Review Article | | Nature Cell Biology

Stem cells in development

Trophoblast and embryonic stem cells interact in vitro to form structures that resemble early blastocysts, and the embryo provides signals that drive early trophectoderm development and implantation.

Letter | | Nature

Kian Peng Koh and colleagues report that TET1 regulates lineage-specific genes in the mouse postimplantation embryo, many of them independently of DNA methylation changes, through regulation of JMJD8 expression. They show that Tet1 deletion causes embryonic defects, which are partially penetrant in an inbred strain but fully lethal in non-inbred mice.

Article | | Nature Genetics

Maria-Elena Torres-Padilla and colleagues use a targeted epigenomic approach to investigate the role of LINE-1 retroelements during early mouse development. Their data suggest that timely activation of LINE-1 regulates global chromatin accessibility and is integral to the mouse developmental program.

Article | | Nature Genetics

Bradley Cairns, Douglas Carrell, Stephen Tapscott and colleagues transcriptionally profile human oocytes and preimplantation embryos and highlight DUX4-family proteins as activators of cleavage-stage genes and repetitive elements. They show that Dux expression converts mouse embryonic stem cells into two-cell (2C) embryo-like cells, thus suggesting mouse DUX and human DUX4 as drivers of the mammalian cleavage/2C state.

Article | | Nature Genetics

Single-cell technologies are transforming our understanding of pre-implantation and early post-implantation development and of in vitro pluripotency. Specifically, single-cell transcriptomics and imaging and the accompanying bioinformatics methods have enabled precision interrogation of cell fate choices and cell lineage diversification, which occur at the level of the individual cell.

Review Article | | Nature Reviews Molecular Cell Biology

The role of stem/progenitor cell populations in mammary gland morphogenesis is not well understood. Here, the authors show that a transcriptional repressor, Blimp1, is expressed in a rare luminal stem cell population, which contribute to duct formation, and survive multiple rounds of pregnancy and involution.

Article | open | | Nature Communications

HoangDinh Huynh and Yihong Wan investigate the role of the mTORC1 pathway during osteoclastogenesis and find that the cytokine RANKL inactivates mTORC1 via calcineurin-mediated dephosphorylation, leading to activation of NFATc1 by reducing its phosphorylation. These findings have implications for bone diseases and mTORC1/NFATc1 signaling.

Article | open | | Communications Biology