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PROVIDER: PRJNA330831 | ENA |
REPOSITORIES: ENA
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Project description:Intronic polyadenylation of PDGFRα in stromal stem cells attenuates muscle fibrosis
| PRJNA322496 | ENA
Project description:The platelet-derived growth factor receptor alpha (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signaling through this receptor promotes muscle development in growing embryos and proper angiogenesis in regenerating adult muscle. However, either increased PDGF ligands or enhanced PDGFRα pathway activity causes pathological fibrosis. This excessive collagen deposition, which is seen in aged and diseased muscle, interferes with proper muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders. Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show that PDGFRα signaling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated. We found that FAPs produce multiple transcriptional variants of PDGFRα with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signaling and to prevent FAP over-activation. Moreover, increasing expression of this isoform limits fibrosis in vivo, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem cell populations. We used microarrays to explore the biological effects of altering intronic polyadenylation of PDGFRα in FAPs in vivo.
2016-11-30 | GSE81744 | GEO
Project description:The platelet-derived growth factor receptor alpha (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signaling through this receptor promotes muscle development in growing embryos and proper angiogenesis in regenerating adult muscle. However, either increased PDGF ligands or enhanced PDGFRα pathway activity causes pathological fibrosis. This excessive collagen deposition, which is seen in aged and diseased muscle, interferes with proper muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders. Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show that PDGFRα signaling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated. We found that FAPs produce multiple transcriptional variants of PDGFRα with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signaling and to prevent FAP over-activation. Moreover, increasing expression of this isoform limits fibrosis in vivo, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem cell populations. We used microarrays to explore the biological effects of altering intronic polyadenylation of PDGFRα in FAPs.
2016-11-30 | GSE60099 | GEO
Project description:PDGFRα+ cells are interstitial/perivascular mesenchymal progenitor cells that have been associated with fibro-adipogenic processes. However, their function during tissue homeostasis or in response to revascularization and regeneration stimuli remains to be fully defined. Here, by high-throughput transcriptomic analysis, adoptive transfer and multicolor lineage tracking we showed that PDGFRα+ cells from skeletal muscle cluster as a population that is transcriptionally distinct from other mesenchymal stromal cells and with an essential role in tissue revascularization and restructuring of ischemic areas. We further showed that tissue regeneration involves the removal of differentiated PDGFRα+-derived cells, while pathological healing occurred if PDGFRα+-derived cells persisted as terminally differentiated mesenchymal cells (e.g. myofibroblasts). From the perspective of tissue regeneration, these studies support a context-dependent 'yin-yang' biology of PDGFRα+ cells, that possess an innate ability to stabilize newly formed blood vessels and concurrently limit injury expansion after ischemia, while also being capable of promoting fibrosis in an unfavorable environment.
2019-07-01 | GSE101930 | GEO
Project description:We utilized a fate-mapping approach to investigate alpha-smooth muscle actin (αSMA)+ and platelet derived growth factor-alpha (PDGFRα)+ cells in two lung fibrosis models, complemented by cell-type specific next-generation sequencing and investigations on human lungs. Our data revealed that αSMA+ and PDGFRα+ cells mark two distinct mesenchymal lineages with minimal transdifferention potential during lung fibrotic remodeling. Parenchymal and perivascular fibrotic regions were populated predominantly with PDGFRα+ cells expressing collagen, while αSMA+ cells in the parenchyma and vessel wall showed variable expression of collagen and the contractile protein desmin. The distinct gene expression profiles found in normal conditions was retained during pathologic remodeling. Cumulatively, our findings identify αSMA+ and PDGFRα+ cells as two separate lineages with distinct gene expression profile in adult lungs.
2019-02-08 | GSE126205 | GEO
Project description:After birth, the intestine undergoes major changes to shift from an immature proliferative state to a functional intestinal barrier. By combining inducible lineage tracing and transcriptomics in mouse models, we identify a pro-differentiation PDGFRαHigh intestinal stromal lineage originating from postnatal LTβR+ perivascular stromal progenitors. Genetic blockage of this lineage increased the intestinal stem cells pool while decreasing epithelial and immune maturation at weaning age, leading to reduced postnatal growth and dysregulated repair responses. Ablating PDGFRα in the LTβR stromal lineage demonstrates that PDGFRα has a major impact on the lineage fate and function, inducing a transcriptomic switch from pro-stemness genes such as Rspo3 and Grem1 to pro-differentiation factors including BMPs, retinoic acid and laminins, and on spatial organization within the crypt-villus and repair responses. Our results show that PDGFRα-induced transcriptomic switch in intestinal stromal cells is required in the first weeks after birth to coordinate postnatal intestinal maturation and function.
2022-05-05 | GSE200364 | GEO
Project description:After birth, the intestine undergoes major changes to shift from an immature proliferative state to a functional intestinal barrier. By combining inducible lineage tracing and transcriptomics in mouse models, we identify a pro-differentiation PDGFRαHigh intestinal stromal lineage originating from postnatal LTβR+ perivascular stromal progenitors. Genetic blockage of this lineage increased the intestinal stem cells pool while decreasing epithelial and immune maturation at weaning age, leading to reduced postnatal growth and dysregulated repair responses. Ablating PDGFRα in the LTβR stromal lineage demonstrates that PDGFRα has a major impact on the lineage fate and function, inducing a transcriptomic switch from pro-stemness genes such as Rspo3 and Grem1 to pro-differentiation factors including BMPs, retinoic acid and laminins, and on spatial organization within the crypt-villus and repair responses. Our results show that PDGFRα-induced transcriptomic switch in intestinal stromal cells is required in the first weeks after birth to coordinate postnatal intestinal maturation and function.
2022-05-05 | GSE200363 | GEO
Project description:After birth, the intestine undergoes major changes to shift from an immature proliferative state to a functional intestinal barrier. By combining inducible lineage tracing and transcriptomics in mouse models, we identify a pro-differentiation PDGFRαHigh intestinal stromal lineage originating from postnatal LTβR+ perivascular stromal progenitors. Genetic blockage of this lineage increased the intestinal stem cells pool while decreasing epithelial and immune maturation at weaning age, leading to reduced postnatal growth and dysregulated repair responses. Ablating PDGFRα in the LTβR stromal lineage demonstrates that PDGFRα has a major impact on the lineage fate and function, inducing a transcriptomic switch from pro-stemness genes such as Rspo3 and Grem1 to pro-differentiation factors including BMPs, retinoic acid and laminins, and on spatial organization within the crypt-villus and repair responses. Our results show that PDGFRα-induced transcriptomic switch in intestinal stromal cells is required in the first weeks after birth to coordinate postnatal intestinal maturation and function.
2022-05-05 | GSE200362 | GEO
Project description:Adipose tissue in the mammary gland undergoes dramatic remodeling during reproduction. Adipocytes are replaced by mammary alveolar structures during pregnancy and lactation, then reappear upon weaning. Here, we reveal that adipocytes in the mammary gland de-differentiate into Pdgfrα+ preadipocyte- and fibroblast-like cells during pregnancy, and remain de-differentiated during lactation. Upon weaning, de-differentiated fibroblasts proliferate and re-differentiate into adipocytes. In order to determine the molecular signature of these de-differentiated adipocytes in the mammary gland, we compared these cells with classical adipocytes. Using the AdipoChaser-mT/mG system, we pre-labeled mature adipocytes with GFP expression to characterize the features of these de-differentiated adipocytes (Figure 4A), and then purified CD31-/CD45-/PDGFRα+/Tomato+ and CD31-/CD45-/PDGFRα+/GFP+ cells from the stromal vascular fraction (SVF) of lactating mammary gland at the peak of lactation through FACS. Gene expression analyses showed that the CD31-/CD45-/PDGFRα+/Tomato+ cells were indeed enriched with Tomato expression, while the CD31-/CD45-/PDGFRα+/GFP+ cells were enriched with GFP expression (Figure 4C). We then collected CD31-/CD45-/PDGFRα+/GFP+ cells as single cells for subsequent single cell RNA-sequencing analysis (Figure 4D-G, Supplemental. Figure S1A-G). After the flow sorting and single cell RNA amplification, 26 CD31-/CD45-/PDGFRα+/GFP+ cells passed the quality control, and these cells were used for single-cell RNA-sequencing analysis. Due to technical difficulties in sorting single mature white adipocyte through flow cytometry, adipocytes differentiated from the immortalized murine-derived brown pre-adipocyte cell line were used as mature adipocyte control (Pradhan et al., 2017). Additionally, we also included population RNA-seq experiments, i.e. three mature white adipocyte samples, two GFP+, and six GFP- ones.
2018-06-17 | E-MTAB-6818 | biostudies-arrayexpress
Project description:Skeletal muscle regeneration is primarily accomplished through the concerted action of the myoblasts as well as the supporting stromal cells. Following accomplishment of injury repair, activated stromal cells disappear via apoptosis. In the case of muscle dystrophies where in a chronic inflammatory environment is present, activated stromal cells are transformed into a myofibroblastic state with the deposition of extracellular matrix components. Excessive accumulation of ECM leads to irreversible fibrosis and tissue deterioration. A distinct stromal cell population named fibro-adipogenic precursors (FAPs) are known to be responsible for contribution to fibrosis and fatty infiltration. Fibrosis is also evident in disuse atrophy and sarcopenia without any significant inflammation. This study aims to analyze the heterogeneous population of FAPs comparatively in the course of acute damage and immobilization models. We isolated and analyzed the mononuclear cell population of skeletal muscles following tenotomy and denervation models in mice. Immunophenotyping of the FAPs was conducted based on exclusion of CD45, CD31 and CD11b and a comparative analysis was accomplished on three different subpopulations of i) CD140a(+), Sca1(+) ii) CD140a(+), Sca1(-) iii) CD140a(-), Sca1(+). High-throughput transcriptome analysis was employed to further characterize the transcriptome of these three cell populations and compare their quiescent and activated states. Results: Investigated sub-populations exhibited diverse activation properties and kinetics for each studied model. While CD140a(+), Sca1(+) was the predominating activated population along with tenotomy, denervation majorly stimulated the proliferation of CD140a(+), Sca1(+) cells. Both immobilization models lacked myofiber damage and exhibited a minute inflammatory response compared to the acute damage. Transcriptome analysis supports commonalities in upregulation of ECM components in diverse subpopulation of cells as well as discriminating candidate cell surface markers. Skeletal muscle regeneration is primarily accomplished through the concerted action of the myoblasts as well as the supporting stromal cells. Following accomplishment of injury repair, activated stromal cells disappear via apoptosis. In the case of muscle dystrophies where in a chronic inflammatory environment is present, activated stromal cells are transformed into a myofibroblastic state with the deposition of extracellular matrix components. Excessive accumulation of ECM leads to irreversible fibrosis and tissue deterioration. A distinct stromal cell population named fibro-adipogenic precursors (FAPs) are known to be responsible for contribution to fibrosis and fatty infiltration. Fibrosis is also evident in disuse atrophy and sarcopenia without any significant inflammation. This study aims to analyze the heterogeneous population of FAPs comparatively in the course of acute damage and immobilization models. We isolated and analyzed the mononuclear cell population of skeletal muscles following tenotomy and denervation models in mice. Immunophenotyping of the FAPs was conducted based on exclusion of CD45, CD31 and CD11b and a comparative analysis was accomplished on three different subpopulations of i) CD140a(+), Sca1(+) ii) CD140a(+), Sca1(-) iii) CD140a(-), Sca1(+). High-throughput transcriptome analysis was employed to further characterize the transcriptome of these three cell populations and compare their quiescent and activated states. Results: Investigated sub-populations exhibited diverse activation properties and kinetics for each studied model. While CD140a(+), Sca1(+) was the predominating activated population along with tenotomy, denervation majorly stimulated the proliferation of CD140a(+), Sca1(+) cells. Both immobilization models lacked myofiber damage and exhibited a minute inflammatory response compared to the acute damage. Transcriptome analysis supports commonalities in upregulation of ECM components in diverse subpopulation of cells as well as discriminating candidate cell surface markers.
2023-01-02 | GSE169411 | GEO