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Hoxa10 mediates positional memory to govern stem cell function in adult skeletal muscle.

ABSTRACT: Muscle stem cells (satellite cells) are distributed throughout the body and have heterogeneous properties among muscles. However, functional topographical genes in satellite cells of adult muscle remain unidentified. Here, we show that expression of Homeobox-A (Hox-A) cluster genes accompanied with DNA hypermethylation of the Hox-A locus was robustly maintained in both somite-derived muscles and their associated satellite cells in adult mice, which recapitulates their embryonic origin. Somite-derived satellite cells were clearly separated from cells derived from cranial mesoderm in Hoxa10 expression. Hoxa10 inactivation led to genomic instability and mitotic catastrophe in somite-derived satellite cells in mice and human. Satellite cell-specific Hoxa10 ablation in mice resulted in a decline in the regenerative ability of somite-derived muscles, which were unobserved in cranial mesoderm-derived muscles. Thus, our results show that Hox gene expression profiles instill the embryonic history in satellite cells as positional memory, potentially modulating region-specific pathophysiology in adult muscles.

SUBMITTER: Yoshioka K

PROVIDER: S-EPMC8189581 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hoxa10 mediates positional memory to govern stem cell function in adult skeletal muscle

Project description:Muscle stem cells (satellite cells) are distributed throughout the body and have heterogeneous properties among muscles. However, functional topographical genes in satellite cells of adult muscle remain unidentified. Here, we show that expression of Homeobox-A (Hox-A) cluster genes accompanied with DNA hypermethylation of the Hox-A locus was robustly maintained in both somite-derived muscles and their associated satellite cells in adult mice, which recapitulates their embryonic origin. Somite-derived satellite cells were clearly separated from cells derived from cranial mesoderm in Hoxa10 expression. Hoxa10 inactivation led to genomic instability and mitotic catastrophe in somite-derived satellite cells in mice and human. Satellite cell–specific Hoxa10 ablation in mice resulted in a decline in the regenerative ability of somite-derived muscles, which were unobserved in cranial mesoderm–derived muscles. Thus, our results show that Hox gene expression profiles instill the embryonic history in satellite cells as positional memory, potentially modulating region-specific pathophysiology in adult muscles.

2021-04-17 | GSE139315 | GEO

Hoxa10 mediates positional memory to govern stem cell function in adult skeletal muscle

Project description:Hoxa10 mediates positional memory to govern stem cell function in adult skeletal muscle

| PRJNA579280 | ENA

Hoxa10 is a functional positional memory that governs stem cell function in adult skeletal muscle

Project description:Skeletal muscle is contractile tissue distributed throughout the body with functionally heterogeneous properties that may relate to region-specific pathophysiology of muscle diseases. Recent studies revealed that muscle stem cells (satellite cells) are a functional heterogeneous population in different muscles, dependent not only on fiber-types but also on embryonic origin. Homeobox (Hox) genes are key regulators of the embryonic body plan. Here, we showed that Hox-A cluster genes are robustly maintained in adult muscles and their associated satellite cells of both mice and humans in a body region-specific manner, whose distribution almost recapitulates their embryonic origin. The region-specific expression of Hox genes was linked to DNA hypermethylation status of Hox-A locus. Importantly, Hox gene expression is a functional memory; Hoxa10 inactivation in satellite cells led to genomic instability and mitotic catastrophe, resulting in a decline in the regionally specific regenerative ability of muscles in mice, even though Hox paralogs are known to be often functionally redundant. Thus, our results demonstrate that the topographic Hox gene expression profile could be a geotagging molecular signature that reflects the anatomical location and embryonic history of resident muscle stem cells, potentially contributing to regionally specific regulations of adult skeletal muscles.

2021-04-16 | GSE154056 | GEO

Hoxa10 is a functional positional memory that governs stem cell function in adult skeletal muscle

Project description:Hoxa10 is a functional positional memory that governs stem cell function in adult skeletal muscle

| PRJNA644944 | ENA

Postnatal memory governs cell function in adult skeletal muscle.

Project description:Skeletal muscle is the contractile tissue that distributes throughout body, with its functionally heterogeneous properties amongst muscles, which may relate to region specific pathology of muscle diseases. Here we found that homeobox (Hox) genes, key regulators of body-plan in the embryo, are region-specifically and robustly maintained as positional memory in both muscle and its associated stem cells named satellite cells in adult mice and humans. Although satellite cell function in adults was unaffected by genetic loss of Hoxa10 in muscle progenitors at the developmental stage, postnatal deletion of Hoxa10 in satellite cells led to genomic instability and mitosis abnormality, resulting in a remarkable decline in regenerative ability of muscles in a region-specific manner. Our results suggest that Hox-based positional memory is flexibly established during embryonic development and governs topographic function of stem cells in adult muscles once it is fixed, potentially influencing the region-specific weakness in muscle diseases

2021-07-08 | GSE139639 | GEO

Distinct Phases of Postnatal Skeletal Muscle Growth Govern the Progressive Establishment of Muscle Stem Cell Quiescence.

Project description:Muscle stem cells (or muscle satellite cells [MuSCs]) are required for postnatal growth. Yet, the detailed characterization of myogenic progression and establishment of quiescence during this process remains poorly documented. Here, we provide an overview of myogenic cells heterogeneity and dynamic from birth to adulthood using flow cytometry. We demonstrated that PAX7+ cells acquire an increasing ability to progress in the myogenic program from birth to adulthood. We then simultaneously analyzed the cycling state (KI67 expression) of the MuSCs and progenitors (PAX7+) and their progression into myogenic precursors (PAX7-MYOD+) and differentiating cells (MYOG+) in vivo. We identified two distinct peaks of myogenic differentiation between P7-P10 and P21-P28, and showed that the quiescent MuSC pool is established between 7 and 8 weeks of age. Overall our study provides a comprehensive in vivo characterization of myogenic heterogeneity and demonstrates the highly dynamic nature of skeletal muscle postnatal growth process.

| S-EPMC7486220 | biostudies-literature

Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis.

Project description:During growth, homeostasis and regeneration, stem cells are exposed to different energy demands. Here, we characterise the metabolic pathways that mediate the commitment and differentiation of mouse skeletal muscle stem cells, and how their modulation can influence the cell state. We show that quiescent satellite stem cells have low energetic demands and perturbed oxidative phosphorylation during ageing, which is also the case for cells from post-mortem tissues. We show also that myogenic fetal cells have distinct metabolic requirements compared to those proliferating during regeneration, with the former displaying a low respiration demand relying mostly on glycolysis. Furthermore, we show distinct requirements for peroxisomal and mitochondrial fatty acid oxidation (FAO) in myogenic cells. Compromising peroxisomal but not mitochondrial FAO promotes early differentiation of myogenic cells. Acute muscle injury and pharmacological block of peroxisomal and mitochondrial FAO expose differential requirements for these organelles during muscle regeneration. Taken together, these observations indicate that changes in myogenic cell state lead to significant alterations in metabolic requirements. In addition, perturbing specific metabolic pathways impacts on myogenic cell fates and the regeneration process.

| S-EPMC6080609 | biostudies-literature

Postnatal memory governs cell function in adult skeletal muscle.

Project description:Postnatal memory governs cell function in adult skeletal muscle.

| PRJNA586756 | ENA

Adult stem cell sources for skeletal and smooth muscle tissue engineering.

Project description:IntroductionTissue engineering is an innovative field with enormous developments in recent years. These advances are not only in the understanding of how stem cells can be isolated, cultured and manipulated but also in their potential for clinical applications. Thus, tissue engineering when applied to skeletal and smooth muscle cells is an area that bears high benefit for patients with muscular diseases or damage. Most of the recent research has been focused on use of adult stem cells. These cells have the ability to rejuvenate and repair damaged tissues and can be derived from different organs and tissue sources. Recently there are several different types of adult stem cells, which have the potential to function as a cell source for tissue engineering of skeletal and smooth muscles. However, to build neo-tissues there are several challenges which have to be addressed, such as the selection of the most suitable stem cell type, isolation techniques, gaining control over its differentiation and proliferation process.ConclusionThe usage of adult stem cells for muscle engineering applications is promising. Here, we summarize the status of research on the use of adult stem cells for cell transplantation in experimental animals and humans. In particular, the application of skeletal and smooth muscle engineering in pre-clinical and clinical trials will be discussed.

| S-EPMC8996587 | biostudies-literature

Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal.

Project description:A central question in stem cell biology is the relationship between stem cells and their niche. Although previous reports have uncovered how signaling molecules released by niche cells support stem cell function, the role of the extra-cellular matrix (ECM) within the niche is unclear. Here, we show that upon activation, skeletal muscle stem cells (satellite cells) induce local remodeling of the ECM and the deposition of laminin-?1 and laminin-?5 into the basal lamina of the satellite cell niche. Genetic ablation of laminin-?1, disruption of integrin-?6 signaling or blocking matrix metalloproteinase activity impairs satellite cell expansion and self-renewal. Collectively, our findings establish that remodeling of the ECM is an integral process of stem cell activity to support propagation and self-renewal, and may explain the effect laminin-?1-containing supports have on embryonic and adult stem cells, as well as the regenerative activity of exogenous laminin-111 therapy.

| S-EPMC5852002 | biostudies-literature

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