Human muscle-derived CLEC14A-positive cells regenerate muscle independent of PAX7
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ABSTRACT:
PROVIDER: PRJNA481958 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7541410_1.fastq.gz | Fastqsanger.gz | |||
| SRR7541410_2.fastq.gz | Fastqsanger.gz | |||
| SRR7541420_1.fastq.gz | Fastqsanger.gz | |||
| SRR7541420_2.fastq.gz | Fastqsanger.gz | |||
| SRR7541411_1.fastq.gz | Fastqsanger.gz |
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Project description:Skeletal muscle stem cells, called satellite cells, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. The transcription factor Pax7 defines satellite cells across species 1-4 . We previously established human PAX7-positive cell colonies with high regenerative potential 5 . We now identified PAX7-negative human muscle-derived cell colonies (PAX7neg) also positive for the myogenic markers desmin and MYF5. These included cells from a unique myopathic patient with rigid spine and respiratory insufficiency due to a homozygous PAX7 c.86-1G>A mutation (PAX7null). Single cell and bulk transcriptome analysis showed high intra- and inter-donor heterogeneity and revealed the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7neg cell populations, including PAX7null, formed myofibers after transplantation into mice, and regenerated muscle after reinjury. Transplanted PAX7neg cells repopulated the satellite cell niche where they re-expressed PAX7. Strikingly, PAX7null cells expressing CLEC14A were also identified below the basal lamina. In summary, transplanted human cells do not depend on PAX7 for muscle regeneration. Thus, Pax7 is not a suitable marker for selection of optimal cells for muscle regenerative therapies.
2019-11-11 | GSE117382 | GEO
Project description:Skeletal muscle stem cells, called satellite cells and defined by the transcription factor PAX7, are responsible for postnatal muscle growth, homeostasis and regeneration. Attempts to utilize the regenerative potential of muscle stem cells for therapeutic purposes so far failed. We previously established the existence of human PAX7-positive cell colonies with high regenerative potential. We now identified PAX7-negative human muscle-derived cell colonies also positive for the myogenic markers desmin and MYF5. These include cells from a patient with a homozygous PAX7 c.86-1G > A mutation (PAX7null). Single cell and bulk transcriptome analysis show high intra- and inter-donor heterogeneity and reveal the endothelial cell marker CLEC14A to be highly expressed in PAX7null cells. All PAX7-negative cell populations, including PAX7null, form myofibers after transplantation into mice, and regenerate muscle after reinjury. Transplanted PAX7neg cells repopulate the satellite cell niche where they re-express PAX7, or, strikingly, CLEC14A. In conclusion, transplanted human cells do not depend on PAX7 for muscle regeneration.
| S-EPMC6920394 | biostudies-literature
Project description:Adult muscle stem cells, also known as muscle satellite cells, which are the resident tissue stem cells of skeletal muscle, provide myonuclei for postnatal muscle growth and for maintenance and regeneration in adults. Satellite cells specifically express the transcription factor pax7. The purpose of this study was to identify pax7 target genes and clarify the role of pax7 in muscle stem cell maintenance. We succeeded in generating Pax7-YFP knockin mice (Pax7-YFP KI) that can visualize endogenous pax7 expressed in satellite cells with YFP fluorescent protein. Novel pax7 target genes were identified by ChIP-sequencing (chromatin immunoprecipitation) analysis with muscle stem cells of Pax7-YFP KI mice.
2023-08-31 | GSE164535 | GEO
Project description:Satellite cells (SC) are muscle stem cells which can regenerate adult muscles upon injury. Most SC originate from PAX7+ myogenic precursors set aside during development. Although myogenesis has been studied in mouse and chicken embryos, little is known about human muscle development. Here, we report the generation of human induced pluripotent stem cell (iPSC) reporter lines in which fluorescent proteins have been introduced into the PAX7 and MYOG loci. We use single cell RNA sequencing to analyze the developmental trajectory of the iPSC-derived PAX7+ myogenic precursors. We show that the PAX7+ cells generated in culture can produce myofibers and self-renew in vitro and in vivo. Together, we demonstrate that cells exhibiting characteristics of human fetal satellite cells can be produced in vitro from iPSC, opening interesting avenues for muscular dystrophy cell therapy. This work provides significant insights into the development of the human myogenic lineage.
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Project description:The mechanisms by which Pax7 promotes skeletal muscle stem (satellite) cell identity are not yet understood. We have taken advantage of pluripotent stem cells wherein the induced expression of Pax7 robustly initiates the muscle program and enables the generation of muscle precursors that repopulate the satellite cell compartment upon transplantation. Pax7 binding was excluded from H3K27 tri-methylated regions, suggesting that recruitment of this factor is circumscribed by chromatin state. Further, Pax7 binding provoked localized chromatin remodeling, including the acquisition of enhancer-associated histone marks and induction of chromatin accessibility. Conversely, removal of Pax7 led to rapid reversal of these features on a subset of enhancers. Another cohort of Pax7 binding sites exhibited a durably accessible and remodeled chromatin state after Pax7 removal, and persistent enhancer accessibility was associated with subsequent binding by muscle regulatory factors. Our studies provide new insights into Pax7 and the epigenetic landscape of skeletal muscle stem cells.
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Project description:To identify Pax7 target genes in muscle progenitor cells, we compared the transcriptome profiles of muscle progenitor cells from young mice (P12) with and without Pax7.
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Project description:It has been suggested that muscle stem cell function is regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. We identified two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD+, were identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis led to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirmed that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Thus, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue.
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Project description:Microarray analysis of rhabdomyosarcomas generated using mice with conditional mutations in Kras and p53 using both in vivo and in vitro approaches to identify a cell of origin for rhabdomyosarcoma. Contains rhabdomyosarcomas derived in vivo using Pax7-CreER mice and in vitro using sorted muscle progenitor cells, UPS derived from intramuscular Adeno-Cre injection, and normal muscle.
2011-01-30 | E-GEOD-25098 | biostudies-arrayexpress
Project description:Our goal was to identify differentially expressed genes in Drosophila muscle when misexpressing the human PAX-FKHR fusion oncoprotein. Using the GAL4-UAS expression system, PAX7-FKHR was misexpressed in differentiating muscle. After 2-3 days of expression larval animals were collected, dissected to remove as much non-muscle internal tissue as possible, mRNA extracted, and expression profiling done with Affy Drosophila 2.0 genome chips
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Project description:Sequencing files, and processed data correspond to Figure 3 of Regenerating Human Skeletal Muscle Forms an Emerging Niche In Vivo to Support PAX7 cells. Data contains single nucleus RNA seq from Pax7 ablated mdx-NSG mice, control mdx-NSG mice, with or without an injury. These mice offer superior engraftment by human skeletal muscle stem and progenitor cells. Pax7 ablation model enables evaluation of human stem cell niche formation in the absence of mouse Pax7 cell competition. Included in this dataset is everything required to run independent analysis. We have included raw Fastq files and processed files that are ready to be uploaded into Loupe Browser or R-Studio/Seurat V3. To summarize Cloupe Files can be uploaded to Loupe Browers and the BC_Matrix.H5 files can be uploaded directly to R. Furthermore, the RDS files are processed R-program files that can be immediately uploaded into R for analysis. We have included an example R script for users to follow and a few PDFs of excepted UMAPs using all combined files at PCA 35.
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