Cockayne syndrome (CS) is a rare autosomal reces-sive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sun-light, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limita-tions of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from ﬁbroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic gene-corrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. CS-associated phenotypic defects are recapit-ulated in CS-iPSC-derived mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display increased susceptibility to DNA damage stress. Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6. We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives (MSCs and NSCs) in the absence or presence of ultraviolet (UV) and replicative stresses, revealing that defects in DNA repair account for CS pathologies. Moreover, we generate autologous GC-MSCs free of pathogenic mutation under a cGMP (Current Good Manufacturing Practice)-compli- ant condition, which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS. Collectively, our models demonstrate novel disease features and molecular mechanisms and lay a founda- tion for the development of novel therapeutic strategies to treat CS.
Diploidy is the typical genomic mode in all mammals. Haploid stem cells are artiﬁcial cell lines experimentally derived invitroin the form of different types of stem cells, which combine the characteristics of haploidy with a broad developmental potential and open the possibil- ity to uncover biological mysteries at a genomic scale. To date, a multitude of haploid stem cell types from mouse, rat, monkey and humans have been derived, as more are in development. They have been applied in high-throughput genetic screens and mammalian assisted reproduction. Here, we review the generation, unique properties and broad applications of these remarkable cells.
Ever since hematopoietic stem cells (HSCs) were first identified half a century ago, their differentiation roadmap has been extensively studied. The classical model of hematopoiesis has long held as a dogma that HSCs reside at the top of a hierarchy in which HSCs possess self-renewal capacity and can progressively give rise to all blood lineage cells. However, over the past several years, with advances in single cell technologies, this developmental scheme has been challenged. In this review, we discuss the evidence supporting heterogeneity within HSC and progenitor populations as well as the hierarchical models revised by novel approaches mainly in mouse system. These evolving views provide further understanding of hematopoiesis and highlight the complexity of hematopoietic differentiation.
Neuropsychiatric disorders are complex disorders characterized by heterogeneous genetic variations, variable symptoms, and widespread changes in anatomical pathology. In the context of neuropsychiatric disorders, limited access to relevant tissue types presents challenges for understanding disease etiology and developing effective treatments. Induced pluripotent stem cells (iPSCs) reprogrammed from patient somatic cells offer an opportunity to recapitulate disease development in relevant cell types, and they provide novel approaches for understanding disease mechanisms and for development of effective treatments. Here we review recent progress and challenges in differentiation paradigms for generating disease-relevant cells and recent studies of neuropsychiatric disorders using human pluripotent stem cell (hPSC) models where cellular phenotypes linked to disease have been reported. The use of iPSC-based disease models holds great promise for understanding disease mechanisms and supporting discovery of effective treatments.
Pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (ntESCs), and induced pluripotent stem cells (iPSCs) have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells. In order to maintain their self-renewal and pluripotency, PSCs need to preserve their telomere length and homeostasis. In recent years, increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process. Telomere-associated proteins are not only required for telomere maintenance in both stem cells, their extra-telomeric functions have also been found to be critical as well. Here, we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency.
Pluripotent stem cells (PSCs) are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body, and thus hold great promise for regenerative medicine. To achieve their clinical potential, it is critical for PSCs to maintain genomic stability during the extended proliferation. The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells. In response to DNA damage or oncogenic stress, p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest, apoptosis, and senescence to prevent the passage of genetic mutations to the daughter cells. p53 is also required to maintain the genomic stability of PSCs. However, in response to the genotoxic stresses, a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency, providing mechanisms to maintain the genomic stability of the self-renewing PSCs. In addition, the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress. In summary, the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.