PDGFRβ+ cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA605108 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11033421.fastq.gz | Fastqsanger.gz | |||
| SRR11033422.fastq.gz | Fastqsanger.gz | |||
| SRR11033423.fastq.gz | Fastqsanger.gz |
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Project description:Hematopoietic stem cell (HSC) generation in the aorta-gonads-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFRβ signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFRβ is involved. Here we show that PDGFRβ is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFRβ+ cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFRβ+ embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of these clinically important cells in vitro.
2022-07-19 | GSE162103 | GEO
Project description:Hematopoietic stem cell (HSC) generation in the aorta-gonads-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFRβ signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFRβ is involved. Here we show that PDGFRβ is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFRβ+ cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFRβ+ embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of these clinically important cells in vitro.
2023-02-05 | GSE144837 | GEO
Project description:PDGFRβ+ cells play a dual role as hematopoietic precursors and niche cells during mouse ontogeny
| PRJNA680583 | ENA
Project description:Hematopoietic stem cell (HSC) generation in the aorta-gonad-mesonephros region requires HSC specification signals from the surrounding microenvironment. In zebrafish, PDGF-B/PDGFRβ signaling controls hematopoietic stem/progenitor cell (HSPC) generation and is required in the HSC specification niche. Little is known about murine HSPC specification in vivo and whether PDGF-B/PDGFRβ is involved. Here, we show that PDGFRβ is expressed in distinct perivascular stromal cell layers surrounding the mid-gestation dorsal aorta, and its deletion impairs hematopoiesis. We demonstrate that PDGFRβ+ cells play a dual role in murine hematopoiesis. They act in the aortic niche to support HSPCs, and in addition, PDGFRβ+ embryonic precursors give rise to a subset of HSPCs that persist into adulthood. These findings provide crucial information for the controlled production of HSPCs in vitro.
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Project description:Activated myofibroblasts play an essential role in tissue fibrogenesis by producing extracellular matrixes (ECM). ECMs replace normal functioning tissue, reducing tissue plasticity and impairing functions of the organ. Recent studies suggested that pericytes are a major source of myofibroblast precursors. We previously showed that Smad Anchor for Receptor Activation (SARA) prevents cellular phenotypic transdifferentiation toward mesenchymal cells, and depletion of SARA induces transdifferentiation of epithelial cells to fibroblast-like phenotype. Here, we generated a transgenic mice that overexpress SARA specifically pericytes by using PDGFRβ-Cre (SARATg, PDGFRβ-Cre). When subjected to either subcutaneous injection of bleomycin or intraperitoneal administration of aristolochic acid, which induces skin and kidney fibrosis, respectively, SARATg, PDGFRβ-Cre mice developed significantly less fibrosis compared to SARAWT, PDGFRβ-Cre mice. To decipher molecular signature and pericyte trajectory under fibrotic conditions and effects of SARA overexpression, we isolated PDGFR+ cells from skin or kidney of SARATg or WT, PDGFRβ-Cre, Z/EG mice with or without fibrotic stimuli and performed scRNAseq analyses. In both skin and kidney sample sets, we found pericytes and immune cell populations are the major cell components among the PDGFR+ GFP+ cells. We found that pericyte populations are divided into canonical and non-canonical sub-populations and the latter has assumed myofibroblast characteristics. Trajectory mapping revealed a single path from canonical to non-canonical pericyte sub-populations and SARA overexpression truncated the trajectory. These results suggest that SARA prevents pericyte transdifferentiation into myofibroblasts under fibrotic condition, and therefore anti-fibrotic.
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Project description:Introduction: Cataracts are the world’s leading cause of reversible blindness. Although cataract formation is commonly initiated by lens fiber cell defects, cataractogenesis can be characterized by aberrant proliferation and migration of lens epithelial cells, particularly in posterior capsule opacification. Subsequent overproduction of extracellular matrix components such as fibronectin and collagen by epithelial cells is associated with fibrosis of the lens. Little is known about the role of platelet-derived growth factor receptor β (PDGFRβ) in lens fibrosis. Here, we investigated mice with a conditional knock-in driving mesenchymal-specific PDGFRβ hyperactivation (Fsp1-cre;Pdgfrb+/D849V), which consistently develop cataracts at a young age. Methods: Lenses from Fsp1-cre;Pdgfrb+/D849V mice and age-matched controls were dissected and visualized via microscopy from 9-15 weeks. Early transcriptional changes were investigated between 10-12 day old Fsp1-cre;Pdgfrb+/D849V and control mice via RNA sequencing followed by gene set enrichment analysis. Confirmation of RNA sequencing results and mechanistic investigation of PDGFRβ-induced cataractogenesis were determined in lenses isolated from 15-week-old Fsp1-cre;Pdgfrb+/D849V and control mice. Results: Gross examination of cataractous lenses from Fsp1-cre;Pdgfrb+/D849V mice revealed complete opacification by 15 weeks of age compared to no opacification in age-matched controls. Structural changes in the anterior, equatorial, and posterior lens were observed in histology. RNA sequencing revealed significant enrichment of gene sets related to extracellular matrix deposition and reorganization. Mechanistic investigation revealed major roles for TGFβ, SOCS2, and STAT5-IGF1 signaling axes in PDGFRβ-induced cataract formation. Conclusion: PDGFRβ promoted cataractogenesis by modulating pro-fibrotic extracellular matrix changes, likely through TGFβ, SOCS2, and the STAT5-IGF1 pathways. Future experiments will delineate the precise role of the STAT5-IGF1 signaling pathway in PDGFRβ-mediated fibrosis and the interplay between PDGFRβ and TGFβ in the lens and whether this signaling is targetable to modulate cataractogenesis.
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Project description:The mechanisms underlying oncogenesis in desmoid-type fibromatosis are poorly understood. This project sought to understand how β-catenin may function to promote desmoid formation and how external signaling by PDGFRβ modulates this activity. To examine this question, RNA-seq was performed on CTNNB1 knock-downs. Gene set enrichment analysis suggested that the oncogene controlled HIF1 and angiogenesis pathways; expression of related genes accurately differentiated desmoids analyzed by U133A array from normal mesenchymal tissues. We identified c-ABL as a direct transcriptional target of β-catenin that promoted HIF1α expression in desmoid cells. We also noted that c-ABL activity was enhanced by PDGFRβ. PDGFRβ enhanced desmoid cell proliferation and c-ABL was necessary for desmoid proliferation. To identify potential markers of PDGFRβ/c-ABL activity in vivo, we assessed RNA-seq of desmoid cells treated with PDGF-BB. ERG1 transcription was highly upregulate and IHC of ERG1 was subsequently used to assess outcomes in desmoid patients with biopsies available for testing.
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Project description:Despite their key role in immunity our understanding of primary and secondary lymphoid stromal cell heterogeneity and ontogeny remains limited. Here, using genome-wide expression profiling and phenotypic and localization studies, we identify a functionally distinct subset of BP3-PDPN+PDGFRβ+/α+CD34+ stromal adventitial cells in both lymph nodes and thymus that is located within the perivascular niche surrounding PDPN-PDGFRβ+/α-Esam-1+ITGA7+ pericytes. In re-aggregate organ grafts adult CD34+ adventitial cells gave rise to multiple thymic and lymph node mesenchymal subsets including pericytes, FRC-, MRC- and FDC-like cells, the development of which was lymphoid environment dependent. During thymic ontogeny pericytes developed from a transient population of BP3-PDPN+PDGFRβ+/α+CD34-/lo anlage-seeding progenitors that subsequently up-regulated CD34 and we provide evidence suggesting that similar embryonic progenitors give rise to lymph node mesenchymal subsets. These findings extend the current understanding of lymphoid mesenchymal cell heterogeneity and highlight a role of the CD34+ vascular adventitia as a potential ubiquitous source of lymphoid stromal precursors in postnatal tissues. To comprehensively study the differences and similarities between mesenchymal stromal subsets in the thymus and lymph nodes, global gene expression analysis was performed on sorted PDPN-, BP-3-PDPN+ and BP-3+PDPN+ PDGFRb+ lymph node mesenchymal cells (LNMC) as well as PDPN- and BP-3-PDPN+ PDGFRb+ thymic mesenchymal cells (TMC) from 2 w old mice by microarray.
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