Stem Cells in Development and Disease

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Today, these induced pluripotent stem cells iPSCs are amongst others utilized to explicitly study human pathomechanisms in a patient specific setting. Moreover, tissue specific stem cell, for example, serving as a cellular reserve and substitute for decayed cells and degenerated tissue, is discussed as a useful source of human tissue and tissue specific cells. Clearly, these adult stem cells have already been successfully used in therapeutic approaches for decades, such as hematopoietic stem cells in bone marrow transplantations. Numerous studies exploiting stem cells have already been published describing distinct pathomechanisms in rare and common diseases, giving hope for future therapeutic startups.

Moreover, in the current decade, the first reports of using PSCs in therapeutic approaches have been announced and further upcoming clinical trials in several organ systems are approved and ready to start. Nevertheless, it is still crucial to thoroughly understand underlying cellular mechanisms and molecular pathways implied in developmental and pathological surroundings. For instance, during germ layer formation, Oct4 and Tbx3 promote mesodermal as well as endodermal fate and limit neuroectoderm differentiation potential. In contrast, Sox2 enhances neuroectoderm specification while restricting mesoderm and endoderm lineage development.

What are stem cells, and what do they do?

Later, these factors are subsequently involved in tissue development. Second, one hallmark of cancer is the ability to reactivate genetic programs known from early development and stem cells. To that end we have gathered a variety of studies under the umbrella of stem cell development and disease to provide a basis to understand the steps from basic stem cell biology, further going to physiological function during development until disturbances in function leading to pathological symptoms.

On the basis of stem cell biology, M. Nawaz et al. Current knowledge includes that stem cells continuously secrete factors into surrounding compartments serving as autocrine as well as paracrine signal modifiers. Moreover, abundance of EVs has been reported that mimic the phenotypes of the cells from which they originate. They hereby seem to play a role in the exchange of genetic information utilizing persistent bidirectional communication. This implies that EVs could regulate stemness, self-renewal, and differentiation in stem cells and their subpopulations.

Developmental and Stem Cell Biology in Health and Disease

A poorly investigated stem cell population is the trophoblast stem cell TSC , responsible for the generation and function of the fetal placenta. Arnold et al. Using a remarkable set of methods and approaches, they broadly contribute to the knowledge on TSCs and provide a well-defined set of markers and transcriptional signatures of these cells.

Moreover, they investigate the time-dependent expression of several genes involved in early differentiation events both on mRNA and protein levels.

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In the field of adult mesenchymal stem cells MSCs , which are still considered as a great hope for a variety of clinical implications, K. Elahi et al. Nevertheless, they point to the fact that these differences could also be a benefit for distinct approaches. For example, subsets of MSCs seem to express distinct and unique sets of surface markers, which might help to find a perfect subpopulation for a respective utilization. In the system of MSCs, S. Wang et al. In terms of MSC differentiation signals, J. Chen et al. Here they explore the role of exogenous heparin sulfate HS in terms of its underlying molecular mechanism in MSC chondrogenesis.

In the neural system, enteric clusters of neurons are crucial to uphold gastrointestinal movement and regulation. Here, P. Neckel et al. They report on differentially regulated genes compared in proliferating and differentiating ENSs involved in pathways such as cell cycle, apoptosis, proliferation, or differentiation. Besides the expected differences in cell cycle regulation they also reported on marked inactivation of the canonical Wnt-pathway after induction of differentiation.

In a second study on the enteric nervous system, K. Nothelfer et al. They investigated the expression of the Wnt receptor frizzled-4 in the human ENS of small and large intestines and found a significant abundance of frizzled-4 in a subpopulation of enteric neuronal and glial cells. Moreover they observe a copositivity of frizzled-4 with neural progenitor markers nestin and p75ntr, implying a role of frizzled-4 during the development of the ENS.

On the reverse developmental pathway describing the reprogramming of somatic cells to induced pluripotent stem cells, a huge number of mechanisms and transcription factors are involved in the turn of maturity to pluripotency. Here, it was already reported that T-box transcription factors play distinct roles in the pluripotency network itself as well as during early steps of development. In this respect, M. Klingenstein et al. This information might fill a gap of knowledge concerning factors involved in both pluripotency and in early steps of cell fate determination, cell development, and adult function.

Signaling pathways and underlying factors represent the crucial set to upkeep stemness in vivo and in vitro. 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.

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.

Defeating Sickle Cell Disease with Stem Cells + Gene Therapy: Stem Cells in Your Face, Episode 2

PSC-based disease models are generated using various strategies and can be used for the discovery of new drugs and therapies. Review Article 16 May Nature. Review Article 9 Nov Nature Biotechnology. This protocol describes the generation of mice entirely derived from genome-edited embryonic stem cells, enabling the production of transgenic mice in a single generation.

Protocol 16 Nov Nature Protocols. 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.

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. An artificial recombination locus, Polylox , that can generate hundreds of thousands of individual barcodes is used to trace the fates of haematopoietic stem cells in mice. Letter 16 Aug Nature.

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 5 Oct Nature. Letter 3 Jan Nature. Single-cell transcriptomics, fate assays and a computational theory enable prediction of cell fates during haematopoiesis, discovery of regulators of erythropoiesis and reveal coupling between the erythroid, basophil and mast cell fates.

Article 21 Feb Nature. Ascorbate depletion in mice increased haematopoietic stem-cell frequency and promoted leukaemogenesis, partly by reducing the function of the Tet2 tumour suppressor enzyme. Article 21 Aug Nature. This paper describes a fully defined, nonxenogeneic in vitro niche for the differentiation of haematopoietic stem and progenitor cells to progenitor T cells in mouse and human.

Article 10 Apr Nature Methods. This paper describes an in vitro method to generate human T cells from hematopoietic stem and progenitor cells HSPCs. It should be useful for both basic and applied studies using T cells. Article 3 Apr Nature Methods. Gutierrez-Martinez et al. Article 12 Mar Nature Cell Biology.

Article 20 Mar Nature Cell Biology. Review Article 24 Jan 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 25 Sep 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. Article 24 Apr 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 15 May 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 9 Oct Nature Medicine. Adult stem cells are essential for the maintenance of tissue homeostasis and wound repair, but cancer can hijack their tissue regenerative functions to promote malignancy. Ge and Fuchs review recent insights into the determinants and general principles underlying stem cell plasticity under homeostasis, stress and cancer.

Stem cells are long-lived and possess unique mechanisms related to quiescence, DNA damage response and apoptosis that protect them throughout their lifespan and during tissue repair. These mechanisms may also have a role in cancer stem cells and tumorigenesis. Opinion 19 Jan Nature Reviews Cancer. Review Article 6 Oct Nature Medicine. Notch signalling is a fundamental negative regulator of epidermal stemness. Individual human epidermal cells differ in their self-renewal ability. Here the authors perform genome-wide pooled RNAi screens to uncover the molecular basis for this heterogeneity, and identify genes conferring a clonal growth advantage on normal and neoplastic human epidermal cells.

This paper reports the efficient generation of human alveolar cells from induced pluripotent stem cells and their expansion in 3D culture. Article 2 Oct Nature Methods. This paper describes methods for the 3D culture of mouse lung progenitor cells that can differentiate in vitro and in vivo along all epithelial lineages.

Article 6 Nov Nature Methods. 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. The role of epigenetic regulation in adult stem cell function depends on the specific tissue and factor, but it commonly affects stem cell maintenance, self-renewal and differentiation without disrupting germ-layer fate. 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. The mechanism by which cell geometry regulates cell signalling is reported to be modulated by lipid rafts within the plasma membrane, which are now shown to be responsible for geometry-dependent mesenchymal stem cell differentiation. Letter 12 Feb Nature Materials.

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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. 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 Access 10 Nov npj Microgravity. Signals from a protein that regulates cell division are essential to maintain the stem cells that regenerate hair follicles. 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.

Letter 26 Apr Nature. Genetic and phenotypic analysis reveals expression quantitative trait loci in human induced pluripotent stem cell lines associated with cancer and disease. Article 10 May 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 9 May Nature. Mouse fibroblasts are reprogrammed to induced pluripotent stem cells using single-chain antibodies in place of transcription-factor genes. Article 11 Sep Nature Biotechnology. Article 15 May Nature Biotechnology. Article 9 Apr Nature Medicine. Article 5 Feb Nature Medicine.

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 15 Jan Nature Genetics. Article 4 Dec 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.

Article 24 Jul 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.

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Article 11 Dec Nature Genetics. Transient transcription factor expression rapidly induces a homogenous population of mature GABAergic neurons from human pluripotent stem cells, aiding the study of inhibitory neuron function and disease. Article 15 May Nature Methods. Combining each sgRNA with a unique molecular identifier in a genome-wide screen increases sensitivity and robustness in both positive and negative selection.

Article 16 Oct Nature Methods. This study compares naive human pluripotent stem cells, either reprogrammed directly from somatic cells or converted from primed cells, under a variety of culture conditions. Analysis 25 Sep Nature Methods. Pastor et al. Article 25 Apr Nature Cell Biology.

Yilmaz et al. Resource 16 Apr Nature Cell Biology.

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Pandya et al. 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 2 Mar Nature Neuroscience. A new chemically defined culture medium for the long-term culture of human pluripotent stem cells uses only three chemical compounds and a lower number of recombinant proteins than used in commercially available media.

Article 5 Mar Nature Biomedical Engineering. Article 3 Oct Nature Biomedical Engineering. Cell state transitions during embryonic development are associated with epigenetic changes that alter chromatin structure and gene expression. Interplay between epigenetic regulatory layers can be studied using genomic technologies and embryonic stem cell cultures that reflect in vivo cell states. 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. 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. Recent advances in our understating of the molecular underpinnings of alternative primed- and naive-like pluripotent states in rodents and humans highlight potential functional benefits of naive pluripotency and identify key unanswered questions in this rapidly evolving field.

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. 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.

Genome editing in human zygotes shows that OCT4 is required for normal development at an earlier stage in humans than in mice.