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Astrocytes abound in the human central nervous system (CNS) and play a multitude of indispensable roles in neuronal homeostasis and regulation of synaptic plasticity. While traditionally considered to be merely ancillary supportive cells, their complex yet fundamental relevance to brain physiology and pathology have only become apparent in recent times. Beyond their myriad canonical functions, previously unrecognised region-specific functional heterogeneity of astrocytes is emerging as an important attribute and challenges the traditional perspective of CNS-wide astrocyte homogeneity. Animal models have undeniably provided crucial insights into astrocyte biology, yet interspecies differences may limit the translational yield of such studies. Indeed, experimental systems aiming to understand the function of human astrocytes in health and disease have been hampered by accessibility to enriched cultures. Human induced pluripotent stem cells (hiPSCs) now offer an unparalleled model system to interrogate the role of astrocytes in neurodegenerative disorders. By virtue of their ability to convey mutations at pathophysiological levels in a human system, hiPSCs may serve as an ideal pre-clinical platform for both resolution of pathogenic mechanisms and drug discovery. Here, we review astrocyte specification from hiPSCs and discuss their role in modelling human neurological diseases.

The revolutionary discovery that somatic cells can be reprogrammed by a defined set transcription factors to induced pluripotent stem cells (iPSCs) changed dramatically the way we perceive cell fate determination. Importantly, iPSCs, similar to embryo-derived stem cells (ESCs), are characterized by a remarkable developmental plasticity and the capacity to self-renew “indefinitely” under appropriate culture conditions, opening new avenues for personalized therapy and disease modeling. Elucidating the molecular mechanisms that maintain, induce, or alter stem cell identity is crucial for a deeper understanding of cell fate determination and potential translational applications. Intense research over the last 10 years exploiting technological advances in epigenomics and genome editing has unraveled many of the mysteries of pluripotent identity enabling novel and efficient ways to manipulate it for biomedical purposes. In this review, we focus on the chromatin and epigenetic characteristics that distinguish stem cells from somatic cells and their dynamic changes during differentiation and reprogramming.

Cellular senescence is a continuous and highly organized process that alters the intricate genomic network in order to maintain cellular homeostasis. It occurs in all primary cell cultures—including mesenchymal stem cells (MSCs), which are concurrently tested for a wide variety of clinical applications. Differentiation potential as well as paracrine secretion of MSCs is severely affected by cellular senescence. There is a growing perception that nuclear reorganization and epigenetic modifications contribute to trigger and maintain functional differences in long-term culture. In this review, we discuss molecular and epigenetic aspects that evoke functional changes in cellular aging—indicating that the underlying process is not only an accumulation of cellular defects, but rather epigenetically orchestrated.

Decline in regenerative capacity due to depletion or dysfunction of stem cells is a prominent hallmark of aging across tissues and organisms. Molecular damages such as protein, organelle, and DNA damages are commonly recognized as drivers of age-related stem cell decline. In this review, we discuss diverse damage types and respective avoidance strategies used by stem cells across species with specific focus on avoidance of genotoxic damage and evasion of DNA-damage induced death. Within DNA damage management by stem cells, protective strategies range from asymmetric damage exclusion to downregulation of DNA damage checkpoints and upregulation of pro-survival factors. We also discuss systemic impact of stem cell DNA damage from the angle of its organ-damaging role and from the unexpected pro-homeostatic angle. We use examples of progeroid syndromes and acute irradiation exposure to outline the impact of stem cell DNA damage on the aging process.

Early during mammalian embryogenesis, epiblast cells undertake major cell fate decisions, becoming specified towards either the perishable soma or the immortal germline. Despite the importance of these developmental transitions, the transcriptional regulatory mechanisms orchestrating them have remained poorly characterized due to the transient nature and scarcity of the involved cell populations. However, our view of these processes is dramatically changing due to advances in mouse and human embryonic stem cell (ESC) differentiation models that faithfully recapitulate peri-implantation transitions. Recent studies using these models have uncovered enhancers as critical cis -regulators during the maintenance, extinction, or re-establishment of pluripotency. Here, we review the major transcriptional and epigenetic regulators controlling the remodeling of enhancer landscapes during mammalian peri-implantation development. Last but not least, we discuss how a global and mechanistic understanding of enhancer remodeling can provide important insights into somatic reprogramming, the molecular basis of aging, and the implementation of cellular rejuvenation strategies.

The adult mammalian central nervous system contains resident neural stem cells able to self-renew and to generate new neurons throughout life, as well as other neural cell types. Progressive changes in adult neural stem cells accompany the aging process, which may contribute to a progressive decline in regenerative capacities, tissue degeneration, and functional impairments. For example, accelerated and pathological declines in neural stem cell functions have been associated with age-related brain diseases. Therefore, identifying and better understanding the age-associated molecular events involved in the deterioration of adult neural stem cell homeostasis is of high interest. To date, several intrinsic and extrinsic factors have been identified as putative drivers for age-related dysfunctions in brain stem cell niches. This review aims to provide a concise overview of the age-associated changes that have been reported in mammalian adult neural stem cells as well as the underlying events able to trigger those changes.

Stem cells are characterized by their ability to asymmetrically divide, generating another self-renewing stem cell and a differentiating daughter cell. They reside within the local niche microenvironment, which, together with systemic signals, regulates intrinsic stem cell function. Stem cells are finely regulated, with even slight deregulation leading to gain of stem cell function and tumorigenesis or loss of stem cell function and tissue degeneration in aging. In this review, we highlight how stem cells are maintained within their niche and what is known about their deregulation in aging. To highlight these points, we look at the Drosophila male germline stem cell niche as a model system, specifically focusing on cell cycle progression, signaling pathways, epigenetics, and the control of spindle orientation by centrosomes. Finally, we sum up pertinent questions to be addressed in understanding stem cell function and their malfunction in aging.

One of the most obvious characteristics of the aging process is the progressive decline in the regenerative potential of tissues. Adult somatic stem cells are critical for rejuvenating tissues and persist throughout the lifespan of organisms. However, stem cell function declines during the aging process in tissues such as the brain, blood, skin, intestinal epithelium, bone, and skeletal muscle. This demise may contribute to tissue degeneration, organismal aging, and age-related diseases. A series of organismal models have emerged as valuable systems to study stem cell aging in vivo. Here, we review the age-associated changes of stem cells and the different organismal models used to define stem cell aging.

Pluripotency is a term in cell biology describing a unique state present in distinct stem cell lines, which were either established from the inner cell mass of the mammalian embryo or derived from somatic cells that have been reprogrammed to induced pluripotent stem cells. Pluripotent stem cells are continuously self-renewing, and their differentiation capacity enables them to develop into all derivatives of the three germ layers of a gastrulating embryo (endoderm, ectoderm, mesoderm). Both human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC) are virtually indistinguishable, at least based on their global RNA expression patterns. Yet, after these in vitro cell cultures have been generated, the cell lines’ pluripotent properties may change considerably on the genetic and/or epigenetic level as a consequence of long-term propagation. Among other unphysiological changes, cell lines might acquire aneuploidies, loose physiological imprinting marks, or develop differentiation biases favoring one cell lineage over the other. As a result, stem cell researchers have to continuously monitor each stem cell line’s integrity, transcriptional profile, and functional properties. Regulatory transcription factors, protein-protein interactions, and signaling networks govern the pluripotent state. As a consequence, emerging small- and large-scale perturbations to these gene regulatory networks mediate the outlined unfavorable changes to the pluripotent phenotype. Here, we describe a reliable bioinformatic framework called PluriTest for confirmation and assessment of pluripotency as an animal-free, fast, and inexpensive way based on genome-wide transcriptional RNA profiles from microarrays. Additionally, we discuss future developments using RNA expression profiling for pluripotency assessment.

Maintenance of pluripotency, lineage commitment and differentiation of mammalian embryonic stem cells into all somatic cell types involves differential regulation of different subsets of genes, as does reprogramming of somatic cells back into a pluripotent state. It is now understood that the three-dimensional organization of the human genome asserts a key role in these processes in two ways. First, by providing a largely invariable scaffold onto which dynamic changes in chromatin may manifest; second, by allowing the spatial clustering of genes contributing to the same functional pathways. In this review, we discuss the rapidly growing volume of literature on the structure-to-function relationship of mammalian genomes as regards key developmental transitions of stem cell populations.