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Stem cells from development to the clinic

Advances in technologies that help to characterize stem cells, including genetic and epigenetic properties and lineage trajectories, have increased our knowledge about their physiological roles and contributions to development, ageing, regeneration and disease. Stem cells, and cells differentiated from them, are now used in vitro and in vivo in a variety of applications, such as disease modelling, drug screening and for transplantations.

Clinical Innovation & Regeneration

Skin organoids generated in vitro from human pluripotent stem cells form complex, multilayered skin tissue with hair follicles, sebaceous glands and neural circuitry, and integrate with endogenous skin when grafted onto immunocompromised mice.

Article | | Nature

hPSCs in culture acquire a more naïve pluripotent state upon tankyrase inhibition. Here, the authors show that tankyrase inhibitor-regulated naïve hiPSCs from diabetic donors generate more vascular progenitors and more efficient engraftment into mouse retina than conventional PSCs.

Article | Open Access | | Nature Communications

What happens to cells on engrafting into the brain in animal models to treat Parkinson’s disease is unclear. Here, the authors use scRNA-seq to examine ventral midbrain (VM)-patterned human embryonic stem cells after functional maturation in a pre-clinical rat model for Parkinson’s disease and identify perivascular-like cells.

Article | Open Access | | Nature Communications

Bone marrow stromal cells (BMSCs) lining sinusoidal blood vessels are mesenchymal cells whose function is critical for the skeleton. Here the authors show that quiescent CXCL12-expressing BMSCs can convert into a skeletal stem cell-like state, and differentiate into cortical bone osteoblasts only in response to injury.

Article | Open Access | | Nature Communications

Myocardial infarction causes damage to the myocardium and vasculature. Here the authors show in a rat model of myocardial infarction that cardiomyocytes derived from human induced pluripotent stem cells combined with a human mesenchymal stem cell-loaded patch lead to improved cardiac function and promote vessel formation.

Article | Open Access | | Nature Communications

Mesenchymal stromal cells enhance bone and cartilage repair, but are limited by poor survival and retention after transplantation. Here, the authors show that synthetic hydrogels presenting integrin-specific peptides enhance the survival and persistence of human mesenchymal stromal cells after transplant, as well as bone repair.

Article | Open Access | | Nature Communications

Primary stem cells have long been used therapeutically for applications such as bone marrow transplantation. This Review discusses how cell-engineering approaches are enabling the development of next-generation stem cell therapies with improved function, specificity and responsiveness, thereby expanding their applications into areas such as delivering drugs and oncolytic viruses to tumours and promoting tissue repair in various diseases.

Review Article | | Nature Reviews Drug Discovery

Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. This Review discusses how these technologies have been applied in hepatology, advancing our understanding of cellular heterogeneity and providing novel insights into liver biology such as metabolic zonation and the mechanisms underpinning liver regeneration.

Review Article | | Nature Reviews Gastroenterology & Hepatology

Organoid technology has emerged as a powerful method for studying gastrointestinal cancers. This Review describes organoid models of gastrointestinal cancers, such as colorectal and liver cancer, and discusses how they can be used in basic and translational research in fields such as drug discovery and personalized medicine.

Review Article | | Nature Reviews Gastroenterology & Hepatology

The capacity to regenerate tissue varies across different species and tissue types. The poor regenerative capacity of organs such as the heart and nervous system contributes to the aetiology of a number of serious diseases, including heart failure and Alzheimer disease. In this Review, Goldman and Poss discuss how genetic programmes of regeneration are regulated and how the control mechanisms might be adapted to treat human disease.

Review Article | | Nature Reviews Genetics

Methods & Computational approaches

Novel methods for tracking the progeny of single cells involve prospective lineage tracing, in which DNA barcodes are introduced into single cells and tracked over time, or retrospective lineage tracing, in which somatic mutations are used as DNA barcodes. These methods improve our understanding of cell fates in development, cell differentiation and tissue regeneration.

Review Article | | Nature Reviews Molecular Cell Biology

Transcriptional and epigenomic profiling of osteoblast and adipocyte differentiation shows that adipogenesis is driven by de novo activation of enhancers, whereas osteogenesis involves preestablished enhancers and depends on the activation of pro-osteogenic and antiadipogenic transcription factors.

Article | | Nature Genetics

A new computational framework, novoSpaRc, leverages single-cell data to reconstruct spatial context for cells and spatial expression across tissues and organisms, on the basis of an organization principle for gene expression.

Article | | Nature

Understanding how cells maintain tissues is challenging. Here, the authors present a single consistent quantitative approach to analyse cell proliferation and lineage tracing data, which shows a single proliferating cell population that maintains epidermal and esophageal epithelial homeostasis.

Article | Open Access | | Nature Communications

The signals regulating the establishment and maintenance of the pluripotent epiblast in human embryos are unclear. Here, the authors use a bioinformatics approach to identify the role of IGF1 in human embryo development, and from this, propose a culture medium with IGF1 together with Activin to sustain hESCs in the absence of FGF.

Article | Open Access | | Nature Communications

Understanding developmental trajectories has recently been enabled by progress in modern lineage-tracing methods that combine genetic lineage analysis with omics-based characterization of cell states (particularly transcriptomes). In this Review, Wagner and Klein discuss the conceptual underpinnings, experimental strategies and analytical considerations of these approaches, as well as the biological insights gained.

Review Article | | Nature Reviews Genetics

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

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

In this Perspective, Lea and Niakan describe advances in CRISPR/Cas9 genome editing techniques and discuss ethical questions and potential clinical implications of this technology.

Perspective | | Nature Cell Biology

Embryogenesis & Development

Matrigel is widely used for cell culture. However, its ill-defined composition, batch-to-batch variability and animal-derived nature lead to experimental uncertainty and a lack of reproducibility. In this Review, we discuss the limitations of Matrigel and highlight synthetic alternatives for stem-cell culture, regenerative medicine and organoid assembly.

Review Article | | Nature Reviews Materials

Organoids are 3D cell culture systems that mimic the structural and functional characteristics of organs. In this Review, the authors discuss the biochemical and mechanical material properties relevant for organoid formation and highlight materials designed with the aim to establish organoid cultures as powerful research platforms.

Review Article | | Nature Reviews Materials

How the shape of the pre-implantation murine embryo changes dramatically upon implantation is unclear. Here, the authors use live imaging with a cdx2-GFP reporter line in combination with loss of function experiments to demonstrate that FGF signalling mediated trophectoderm morphogenesis orchestrates this process.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Matthew Quinn et al showed diminished hepatic stress responses in pregnant mice due to epigenetic-mediated decreases in glucocorticoid receptor expression. This decrease is necessary for fetal development and highlights the importance of understanding the tissue-specific effects of glucocorticoid activation in models of maternal stress.

Article | Open Access | | Communications Biology

Naoko Kogata et al. generated murine mammary progenitor cell lines that form spheres and secrete milk upon hormonal stimulation. Deletion of Sox9 increased the ability of these cells to forms spheres but decreased milk production induced by lactogenic stimuli, consistent with the role of this transcription factor on maintaining the stem cell state.

Article | Open Access | | Communications Biology

This Review summarizes our current understanding of the molecular, genetic and epigenetic regulation of normal placentation, largely based on insights from the mouse model, and outlines the new opportunities provided by recent successes in deriving human trophoblast stem cells.

Review Article | | Nature Reviews Genetics

Stem Cells & Ageing

Tumor-reactive T cells are generated by coculturing tumor organoids and autologous peripheral blood lymphocytes and are evaluated for their capacity to carry out effector functions after recognition of tumor cells and whether they kill tumor organoids.

Protocol | | Nature Protocols

Moïra Rossitto et al. find that exposure of pregnant mice to acetaminophen and ibuprofen leads to delayed meiosis in the germline of female offspring and accelerated ovarian aging in F2 females. Their results suggest the use of these analgesics in pregnancy may adversely affect female reproductive health spanning multiple generations.

Article | Open Access | | Communications Biology

Wilkinson and colleagues discuss haematopoietic stem cell (HSC) self-renewal in mice and humans. Experimental techniques for assaying HSC self-renewal are addressed, along with biological mechanisms regulating HSC self-renewal in vivo and ex vivo, and the therapeutic implications of this understanding.

Review Article | | Nature Reviews Genetics

Ageing is characterized by the functional decline of tissues and organs and increased risk of ageing-associated disorders, and this decline is associated with epigenetic changes. Recently, ‘rejuvenating’ interventions, such as metabolic manipulation, partial cell reprogramming, heterochronic parabiosis and senescent cell ablation, have been proposed to extend healthspan and lifespan by modulating the epigenome.

Review Article | | Nature Reviews Molecular Cell Biology