Transciptional profile of pericytes and stromal cells in bleomycin lung injury
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ABSTRACT:
PROVIDER: PRJNA766070 | ENA |
REPOSITORIES: ENA
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Project description:We previously showed that pericyte-like cells derived from the FoxD1-lineage contribute to myofibroblasts following bleomycin-induced lung injury. However, their functional significance in lung fibrosis remains unknown. In this study, we used a model of lung pericyte-like cell ablation to test the hypothesis that pericyte-like cell ablation attenuates lung fibrosis in bleomycin-induced lung injury. Methods: Lung fibrosis was induced by intratracheal instillation of bleomycin. To ablate pericyte-like cells in the lung, diphtheria toxin (DT) was administered to Foxd1-Cre;Rosa26-iDTR mice at two different phases of bleomycin-induced lung injury. For early ablation, we co-administered bleomycin with DT and harvested mice at days 7 and 21. To test the effect of ablation after acute injury, we delivered DT 7 days after bleomycin administration. We assessed fibrosis by lung hydroxyproline content and semiquantitative analysis of picrosirius red-staining. We performed bronchoalveolar lavage to determine cell count and differential. We also interrogated genome-wide mRNA expression at day 7 post injury in whole lung RNA. We focused on the following cell populations for the transcriptional profiling experiments: FoxD1-derived+/Coll-GFP– pericytes (Peri), FoxD1-derived+/Coll-GFP+ pericytes (PeriFibro), and FoxD1-derived–/Coll-GFP+ stromal fibroblasts (Fibro).Results: Compared to DT-insensitive littermates where pericyte-like cells were not ablated, DT-sensitive animals exhibited no difference in fibrosis at day 21 both in the early and late pericyte ablation models. However, early ablation of pericytes reduced acute lung inflammation, as indicated by decreased inflammatory cells. Our data confirm a role for pericytes in regulating pulmonary inflammation in early lung injury.
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Project description:Functional revascularization is key to stroke recovery and requires remodelling of blood vessels, around which is located the brain’s only stromal compartment. Stromal progenitor cells (SPC) form a functional grouping of cells critical for tissue regeneration following injury in many organs, yet their identity in the brain remains elusive despite implications in neovascularization and scar formation. Here we show that the perivascular niche of brain SPCs includes pericytes, venular smooth muscle cells and a distinct population of perivascular fibroblasts, that together help regenerate the cerebral microvasculature following stroke. The ischemic injury triggers amplification of pericytes and perivascular fibroblasts in the infarct region where they associate with endothelial cells inside a reactive astrocyte border. Fate-tracking of Hic1+ SPCs uncovers a transient functional and transcriptional phenotype of stroke-activated pericytes and perivascular fibroblasts, where both populations remain segregated, displaying dichotomous angiogenic and fibrogenic profiles. In the adult brain, pericytes and perivascular fibroblasts are therefore distinct subpopulations of stromal progenitors that coordinate revascularization and scar formation after injury.
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Project description:Analysis of epigenetic changes of pericytes after ischemia-reperfusion renal injury. The hypothesis tested in the present study was that epigenetic change develope in pericytes after acute kidney injury. This phenotype change would cause pericyte to be more proliferative and profibrotic. Results provide important information of the epigenetic change of pericytes, such as specific mechano-responsive genes, up-regulated specific proliferative and profibrotic functions.
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Project description:Two single-cell RNA sequencing data sets were generated called "Whole lung" and "High Resolution". The "Whole lung" single-cell mRNAseq libraries were generated with Drop-Seq from whole mouse lungs upon bleomycin-induced injury and followed over time. Samples were taken at days 3 (n = 3), 7 (n = 5), 10 (n = 3), 14 (n = 4), 21 (n = 4) and 28 (n = 2). Control samples (n = 7) were administered saline only, also indicated with PBS or day0. The "High resolution" single-cell mRNAseq libraries were generated with Drop-Seq from the epithelial compartment of mouse lungs upon bleomycin-induced injury and followed over time. Samples were taken daily for two weeks and at days 21, 28, 36, 54 after injury. Control samples (n = 2) were administered saline only, also indicated with PBS or day0.
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Project description:Epigenetic changes of pericytes after ischemia-reperfusion renal injury
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Project description:Bleomycin-induced acute lung injury is characterized by mesenchymal cell activation, which leads to pulmonary fibrosis. They also have the potential to increase epithelial cells to regenerate alveolar epithelial cell integrity. We used microarrays to detail the change of global gene expression in lung mesenchymal cells in this process.
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Project description:Fibrotic scar tissue formation is conserved throughout the central nervous system in humans and mice, and impairs tissue regeneration and functional recovery. However, the origin of scar-forming stromal fibroblasts is controversial. Here, we show that stromal fibroblasts found after spinal cord injury derive from two populations of perivascular cells that are anatomically and transcriptionally defined as pericytes and perivascular fibroblasts. We identify two distinct perivascular cell populations, which activate and transcriptionally converge on the generation of stromal myofibroblasts after injury. Our results suggest potential targets to improve tissue regeneration and functional recovery after central nervous system injuries.
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Project description:Fibrotic scar tissue formation is conserved throughout the central nervous system in humans and mice, and impairs tissue regeneration and functional recovery. However, the origin of scar-forming stromal fibroblasts is controversial. Here, we show that stromal fibroblasts found after spinal cord injury derive from two populations of perivascular cells that are anatomically and transcriptionally defined as pericytes and perivascular fibroblasts. We identify two distinct perivascular cell populations, which activate and transcriptionally converge on the generation of stromal myofibroblasts after injury. Our results suggest potential targets to improve tissue regeneration and functional recovery after central nervous system injuries.
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Project description:Fibrotic scar tissue formation is conserved throughout the central nervous system in humans and mice, and impairs tissue regeneration and functional recovery. However, the origin of scar-forming stromal fibroblasts is controversial. Here, we show that stromal fibroblasts found after spinal cord injury derive from two populations of perivascular cells that are anatomically and transcriptionally defined as pericytes and perivascular fibroblasts. We identify two distinct perivascular cell populations, which activate and transcriptionally converge on the generation of stromal myofibroblasts after injury. Our results suggest potential targets to improve tissue regeneration and functional recovery after central nervous system injuries.
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