Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Regulation of muscle stem cell function by Mpp7, Amot, Yap and Taz

ABSTRACT: Coordinating mechanical sensing and transcription activation is essential for muscle stem cell (MuSC) function during muscle regeneration. Here we report that MPP7, localized at the apical side of quiescent MuSCs, is an important regulator in MuSC activation, including proliferation and self-renewal. Mechanistically, MPP7 translocates to cell nucleus in response to the change of actin polymerization state with its binding partner AMOT (an actin binding protein) upon MuSC activation and acts to enhance the transcription activity of YAP and TAZ in the MuSC. RNA-seq of MuSCs isolated from control (Con), Mpp7 conditional knockout (cKO), Amot cKO, and Yap and Taz double cKO (YapTaz cKO) after 48 hrs in culture (for activation) in 2 replicas was used to determine the downtream genes regulated by Mpp7, Amot, Yap and Taz. Carm1 was one of the commonly shared down-regulated genes in all 3 cKOs and has been shown to be critical for MuSC self-renewal. We further demonstrated that the MPP7-PDZ domain interacts with TAZ indirectly via AMOT, and the MPP7-L27 domain cooperates with TAZ and another trsncription factor YY1 to regulate a select set of donwstream genes, including Carm1, for MuSC proliferation and self-renewal. Our data identified a coordinated molecular network from mechanical sensing to transcription regulation for MuSC function during muscle regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE241340 | GEO | 2023/10/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation

Project description:Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positional Hox codes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.

2020-09-30 | GSE154813 | GEO

GLUD1 determines murine muscle stem cell fate by controlling mitochondrial glutamate levels

Project description:Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the TCA cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalised myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment specific metabolic brake on MuSC differentiation.

2024-07-02 | GSE243640 | GEO

A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (ChIP-seq)

Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. ChIP-Seq experiments for MYC-HA (HA-IP) performed in IMEC primary breast epithelial cells. Input-samples were sequenced as controlls.

2015-10-28 | E-GEOD-66252 | biostudies-arrayexpress

Autonomous extracellular matrix remodeling controls a progressive adaptation in muscle stem cell regenerative capacity during development

Project description:Muscle stem cells (MuSC) exhibit distinct behaviors during successive phases of developmental myogenesis. However, how their transition to adulthood is regulated is poorly understood. Here we show that fetal MuSC resist progenitor specification and exhibit altered division dynamics, intrinsic features that are progressively lost postnatally. Following transplantation, fetal MuSC more efficiently expand and contribute to muscle repair. Conversely, the efficiency of niche colonization increases in adulthood, indicating a balance between muscle growth and stem cell pool repopulation. Gene expression profiling identified several extracellular matrix (ECM) molecules preferentially expressed in fetal MuSC, including tenascin-C, fibronectin and collagen VI. Loss-of-function experiments confirmed their essential and stage-specific role in regulating MuSC function. Finally, fetal-derived paracrine factors were able to enhance adult MuSC regenerative potential. Together, these findings demonstrate that MuSC change the way in which they remodel their microenvironment to direct stem cell behavior in support of the unique demands of muscle development or repair. MuSCs were isolated through fluorescent-activate cell sorting usinf alpha7-integirn and CD34 as markers to identify the cell population. Total mRNA was then isolated, and samples at different developmental times were compared.

2016-01-20 | E-GEOD-76989 | biostudies-arrayexpress

Changes of the muscle stem cell niche during aging

Project description:During aging, the regenerative capacity of skeletal muscle decreases due to intrinsic changes in muscle stem cells (MuSCs) and alterations in their niche. Here, we used quantitative mass spectrometry to characterize intrinsic changes in the MuSC proteome and remodeling of the MuSC niche during aging. We generated a network connecting age-affected ligands located in the niche and cell surface receptors on MuSCs. Thereby, we revealed signaling via Integrins, Lrp1, Egfr and Cd44 as the major cell communication axes perturbed through aging. We investigated the effect of Smoc2, a secreted protein that accumulates with aging, originating from fibro-adipogenic progenitors. Increased levels of Smoc2 contribute to the aberrant Itgb1/MAPK signaling observed during aging, thereby causing impaired MuSC functionality and muscle regeneration. By connecting changes in the proteome of MuSCs to alterations of their niche, our work will enable a better understanding of how MuSCs are affected during aging.

2021-11-10 | PXD023628 | Pride

Changes of the muscle stem cell niche during aging

2021-11-10 | PXD023643 | Pride

Hydrogel biomaterials that stiffen and soften on demand reveal that skeletal muscle stem cells harbor a mechanical memory

Project description:Muscle stem cells (MuSCs) are specialized cells that reside in adult skeletal muscle poised to repair muscle tissue. The ability of MuSCs to regenerate damaged tissues declines markedly with aging and in diseases such as Duchenne muscular dystrophy, but the underlying causes of MuSC dysfunction remain poorly understood. Both aging and disease result in dramatic increases in the stiffness of the muscle tissue microenvironment from fibrosis. MuSCs are known to lose their regenerative potential if cultured on stiff plastic substrates. We sought to determine if muscle stem cells harbor a memory of their past microenvironment and if it can be overcome. We tested MuSCs in situ using dynamic hydrogel biomaterials that soften or stiffen on demand in response to light and found that freshly isolated MuSCs develop a persistent memory of substrate stiffness characterized by loss of proliferative progenitors within the first three days of culture on stiff substrates. MuSCs cultured on soft hydrogels had altered cytoskeletal organization and activity of Rho and Rac GTPase and YAP mechanotransduction pathways compared to those on stiff hydrogels. Pharmacologic inhibition identified RhoA activation as responsible for the mechanical memory phenotype, and single cell RNA sequencing revealed a molecular signature of the mechanical memory. These studies highlight that microenvironmental stiffness regulates MuSC fate and leads to MuSC dysfunction that is not readily reversed by changing stiffness. Our results suggest that stiffness can be circumvented by targeting downstream signaling pathways to overcome stem cell dysfunction in aged and disease states with aberrant fibrotic tissue mechanics.

2024-08-07 | GSE263619 | GEO

Sex hormones control muscle stem cells

Project description:Quiescent adult muscle stem cells (MuSCs) regenerate skeletal muscle upon injury throughout life. However, aged skeletal muscles fail to maintain stem cell quiescence, leading to declines in MuSC number and functionality. Although autophagy plays an important role in the maintenance of MuSC quiescence, how quiescent MuSCs and their autophagy levels are maintained throughout life is largely unknown. The current study reveals how GnRH, a hypothalamic hormone, maintains the quiescence of adult MuSCs by preventing the onset of senescence and how the decline of sex steroids in organismal ageing is implicated in MuSC ageing.

2019-10-05 | GSE121016 | GEO

A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (RNA-seq)

Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. RNA-Seq Experiments in 2 different primary breast epithelial cell lines (HMLE, which were sorted according to CD44/CD24 surface markers & unsorted IMEC). Both cell lines expressed a doxycycline-inducible version of MYC. For the HMLE cell line DGE analysis was performed for the uninduced (EtOH) situation, comparing CD44high vs CD44 low and for the induced situation Dox vs. EtOH for the CD44high population. For the IMEC cell line DGE was performed by comparing Dox-treated populations expressing either Dox-inducible MYC or a vector control which allows to filter out potential effects due to doxycycline treatment.

2015-10-28 | E-GEOD-66250 | biostudies-arrayexpress

Gli1 marks a sentinel muscle stem cell population for muscle regeneration

Project description:Adult skeletal muscle regeneration is mainly driven by muscle stem cells (MuSCs), which are highly heterogeneous. Although recent studies have started to characterize the heterogeneity of MuSCs, whether a subset of cells with distinct exists within MuSCs remains unanswered. Here, we found that a population of MuSCs, marked by Gli1 expression, is required for muscle regeneration. The Gli1+ MuSC population displayed advantages in proliferation and differentiation both in vitro and in vivo. Depletion of this population led to delayed muscle regeneration, while transplanted Gli1+ MuSCs supported muscle regeneration more effectively than Gli1- MuSCs. Further analysis revealed that even in the uninjured muscle, Gli1+ MuSCs had elevated mTOR signaling activity, increased cell size and mitochondrial numbers compared to Gli1- MuSCs, indicating Gli1+ MuSCs are displaying the features of primed MuSCs. Moreover, Gli1+ MuSCs greatly contributed to the formation of GAlert cells after muscle injury. Collectively, our findings demonstrate that Gli1+ MuSCs represent a distinct MuSC population which is more active in the homeostatic muscle and enters the cell cycle shortly after injury. This cell population functions as the tissue-resident sentinel that rapidly responds to injury and initiates muscle regeneration.

2023-08-06 | GSE239944 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data