Cell stem cell最新文献

Mesenchymal stem cells (MSCs) reside in niches to maintain tissue homeostasis and contribute to repair and regeneration. Although the physiological functions of blood and lymphatic vasculature are well studied, their regulation of MSCs as niche components remains largely unknown. Using adult mouse incisors as a model, we uncover the role of Trp53 in regulating vascular composition through THBS2 to maintain mesenchymal tissue homeostasis. Loss of Trp53 in GLI1+ progeny increases arteries and decreases other vessel types. Platelet-derived growth factors from arteries deposit in the MSC region and interact with PDGFRA and PDGFRB. Significantly, PDGFRA+ and PDGFRB+ cells differentially contribute to defined cell lineages in the adult mouse incisor. Collectively, our results highlight Trp53’s importance in regulating the vascular niche for MSCs. They also shed light on how different arterial cells provide unique cues to regulate MSC subpopulations and maintain their heterogeneity. Furthermore, they provide mechanistic insight into MSC-vasculature crosstalk.

Stem cell therapy has emerged as a promising area of scientific investigation, sparking considerable interest, especially in spinal cord injury (SCI). Sun et al.¹ discover that the extracellular matrix (ECM) from the neonatal spinal cord transmits biochemical signals to endogenous axons, thus promoting axonal regeneration.

Post-implantation, the pluripotent epiblast in a human embryo forms a central lumen, paving the way for gastrulation. Osmotic pressure gradients are considered the drivers of lumen expansion across development, but their role in human epiblasts is unknown. Here, we study lumenogenesis in a pluripotent-stem-cell-based epiblast model using engineered hydrogels. We find that leaky junctions prevent osmotic pressure gradients in early epiblasts and, instead, forces from apical actin polymerization drive lumen expansion. Once the lumen reaches a radius of ∼12 μm, tight junctions mature, and osmotic pressure gradients develop to drive further growth. Computational modeling indicates that apical actin polymerization into a stiff network mediates initial lumen expansion and predicts a transition to pressure-driven growth in larger epiblasts to avoid buckling. Human epiblasts show transcriptional signatures consistent with these mechanisms. Thus, actin polymerization drives lumen expansion in the human epiblast and may serve as a general mechanism of early lumenogenesis.

Development of embryonic stem cells (ESCs) into neurons requires intricate regulation of transcription, splicing, and translation, but how these processes interconnect is not understood. We found that polypyrimidine tract binding protein 1 (PTBP1) controls splicing of DPF2, a subunit of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. Dpf2 exon 7 splicing is inhibited by PTBP1 to produce the DPF2-S isoform early in development. During neuronal differentiation, loss of PTBP1 allows exon 7 inclusion and DPF2-L expression. Different cellular phenotypes and gene expression programs were induced by these alternative DPF2 isoforms. We identified chromatin binding sites enriched for each DPF2 isoform, as well as sites bound by both. In ESC, DPF2-S preferential sites were bound by pluripotency factors. In neuronal progenitors, DPF2-S sites were bound by nuclear factor I (NFI), while DPF2-L sites were bound by CCCTC-binding factor (CTCF). DPF2-S sites exhibited enhancer modifications, while DPF2-L sites showed promoter modifications. Thus, alternative splicing redirects BAF complex targeting to impact chromatin organization during neuronal development.

Recently in Cell Metabolism, Wei et al.¹ unveiled a brain-to-gut pathway that conveys psychological stress to intestinal epithelial cells, leading to their dysfunction. This gut-brain axis involves a microbial metabolite, indole-3-acetate (IAA), as a niche signal that hampers mitochondrial respiration to skew intestinal stem cell (ISC) fate.

In mammals, the circadian clock network drives daily rhythms of tissue-specific homeostasis. To dissect daily inter-tissue communication, we constructed a mouse minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By transcriptomic and functional characterization of this isolated connection, we identified a gatekeeping function of the peripheral tissue clock with respect to systemic inputs. The epidermal clock concurrently integrates and subverts brain signals to ensure timely execution of epidermal daily physiology. Timely cell-cycle termination in the epidermal stem cell compartment depends upon incorporation of clock-driven signals originating from the brain. In contrast, the epidermal clock corrects or outcompetes potentially disruptive feeding-related signals to ensure the optimal timing of DNA replication. Together, we present an approach for cataloging the systemic dependencies of daily temporal organization in a tissue and identify an essential gate-keeping function of peripheral circadian clocks that guarantees tissue homeostasis.

Cancer stemness is recognized as a key component of tumor development. Previously coined “cancer stem cells” (CSCs) and believed to be a rare population with rigid hierarchical organization, there is good evidence to suggest that these cells exhibit a plastic cellular state influenced by dynamic CSC-niche interplay. This revelation underscores the need to reevaluate the hallmarks of cancer stemness. Herein, we summarize the techniques used to identify and characterize the state of these cells and discuss their defining and emerging hallmarks, along with their enabling and associated features. We also highlight potential future directions in this field of research.

Using a human stem cell-based model to understand how the human epiblast forms at the very beginning of implantation, Indana et al.¹ establish a role for pushing forces that are generated by apical actin polymerization and reveal a two-stage, biomechanics-driven lumen growth process underlying epiblast cavity morphogenesis.

Poorly regenerative organs deposit scar tissue to mend damage. Aggarwal et al. establish that transient Sox9 activity is necessary for early proximal tubule epithelial regeneration, while Trogisch et al. and Aggarwal et al. show that persistent Sox9 activity in epithelial and endothelial cells activates fibroblasts creating fibrotic microdomains in multiple organs.