Project description:Adult tissue stem cells (SCs) reside in niches, which, through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single-cell RNA-seq, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage tracing, temporal single-cell analyses, and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged unilineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: some progenitors specify lineages immediately, whereas others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.
Project description:Adult tissue stem cells (SCs) reside in niches, which through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single cell RNA-sequencing, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage-tracing, temporal single cell analyses and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged uni-lineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: Some progenitors specify lineages immediately; others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.
Project description:Adult tissue stem cells (SCs) reside in niches, which through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single cell RNA-sequencing, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage-tracing, temporal single cell analyses and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged uni-lineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: Some progenitors specify lineages immediately; others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.
Project description:Adult tissue stem cells (SCs) reside in niches, which through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single cell RNA-sequencing, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage-tracing, temporal single cell analyses and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged uni-lineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: Some progenitors specify lineages immediately; others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.
Project description:Therapeutic effects of mesenchymal stem cell (MSC) infusion have been revealed in various human disorders, but impacts of diseased micro-environments are only beginning to be noticed. Donor diabetic hyperglycemia is reported to impair therapeutic efficacy of stem cells. However, whether recipient diabetic condition also affects MSC-mediated therapy is unknown. We and others have previously shown that MSC infusion could cure osteopenia, particularly in ovariectomized (OVX) mice. Here, we discovered impaired MSC therapeutic effects on osteopenia in recipient type 1 diabetes (T1D). Through intensive glycemic control by daily insulin treatments, therapeutic effects of MSCs on osteopenia were maintained. Interestingly, by only transiently restoration of recipient euglycemia using single insulin injection, MSC infusion could also rescue T1D-induced osteopenia. Conversely, under recipient hyperglycemia induced by glucose injection in OVX mice, MSC-mediated therapeutic effects on osteopenia were diminished. Mechanistically, recipient hyperglycemic micro-environments reduce anti-inflammatory capacity of MSCs in osteoporotic therapy through suppressing MSC interaction with T cells via the Adenosine monophosphate-activated protein kinase (AMPK) pathway. We further revealed in diabetic micro-environments, double infusion of MSCs ameliorated osteopenia by anti-inflammation, attributed to the first transplanted MSCs which normalized the recipient glucose homeostasis. Collectively, our findings uncover a previously unrecognized role of recipient glycemic conditions controlling MSC-mediated therapy, and unravel that fulfillment of potent therapeutic effects of MSCs requires tight control of recipient micro-environments.
Project description:Bone regeneration originates from proliferation and differentiation of osteoprogenitors via either endochondral or intramembranous ossification; and the regeneration capacities decline with age and estrogen loss. Maxillary sinus floor lifting (MSFL) is a commonly used surgical procedure for guiding bone regeneration in maxilla. Radiographic analysis of 1210 clinical cases of maxilla bone regeneration after MSFL revealed that the intrasinus osteogenic efficacy was independent of age and gender, however; and this might be related to the Schneiderian membrane that lines the sinus cavity. In view of the particularity of this biological process, our present study aimed to elucidate the underlying mechanism of MSFL-induced bone regeneration. We first established a murine model to simulate the clinical MSFL. By single-cell RNA-sequencing and flow cytometry-based bulk RNA-sequencing, we identified a novel Krt14+Ctsk+ subset of cells that display both epithelial and mesenchymal properties and the transcriptomic feature of osteoprogenitors. Dual recombinases-mediated lineage tracing and loss-of-function analyses showed that these Krt14+Ctsk+ progenitors contribute to both MSFL-induced osteogenesis and physiological bone homeostasis by differentiating into Krt14-Ctsk+ descendants which show robust osteogenic capacity. In addition, we detected a similar population of Krt14+Ctsk+ cells in human samples of Schneiderian membrane, which show a highly similar osteogenic potential and transcriptomic feature to the corresponding cells in mice. The identification of this Krt14+Ctsk+ population, featured by osteoprogenitor characteristics and dual epithelial-mesenchymal properties, provides new insight into the understanding of bone regeneration and may open more possibilities for clinical applications.
Project description:The spatial localization of hematopoietic stem cells (HSCs) in the bone marrow (BM) remains controversial, with some studies suggesting that they are maintained in homogeneously distributed niches while others have suggested the contributions of distinct niche structures. Subsets of quiescent HSCs have been reported to associate with megakaryocytes (MK) or arterioles in the BM. However, these HSC subsets have not been prospectively defined. Here, we show that platelet and myeloid-biased HSCs, marked by von Willebrand factor (vWF) expression, are highly enriched in MK niches. Depletion of MK selectively expands vWF+ HSCs, whereas the depletion of NG2+ arteriolar niche cells selectively depletes vWF- lymphoid-biased HSCs. In addition, MK depletion compromises vWF+ HSC function by reducing their long-term self-renewal capacity and eliminating their lineage bias after transplantation. These studies demonstrate the existence of two spatially and functionally separate BM niches for HSC subsets with distinct developmental potential.