Endothelial CXCL12 regulates neovascularization during tissue repair and tumor progression
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ABSTRACT:
PROVIDER: PRJNA610820 | ENA |
REPOSITORIES: ENA
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Project description:Tissue repair and tumor progression are linked by their reliance on the response to ischemia. Coordinated interplay between resident and circulating cells, governed by a myriad of factors, is critical for new blood vessel formation and tissue survival in both. The vascular endothelium exhibits paracrine activity and provides an interface for the recruitment of circulating cells, which in turn influence the neovascularization and extra-vascular tissue growth. CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1 [SDF-1]) has been implicated in tumor biology and neovascularization, but its specific role and mechanism of action remain poorly understood. We have previously demonstrated that CXCL12 expression is hypoxia responsive and occurs in vascular endothelium. Here we use a conditional CXCL12 knockout mouse to show that endothelial-specific deletion of CXCL12 (eKO) reduces the survival of ischemic tissue, which alters both tissue repair and tumor progression. The loss of vascular endothelial CXCL12 disrupts endothelial – fibroblast crosstalk necessary for stromal growth and vascularization. Using single-cell gene expression analysis in combination with a parabiosis model, eKO is found to impair the recruitment of a specific population of non-inflammatory circulating cells defined by genes regulating cell survival and neovascularization. These findings indicate an essential role of endothelial CXCL12 expression during the adult neovascular response in tissue injury and tumor progression, paving the way for future therapeutic interventions.
2020-03-07 | GSE146529 | GEO
Project description:In adults, there is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury, however, molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to a large number of lung diseases in children, indicating a need to uncover fetal programs that promote pulmonary vascular growth. To address this, we used a transgenic mouse reporter for expression of Cxcl12, an arterial hallmark gene, and performed single-cell RNA sequencing on isolated Cxcl12-DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation, gene ontology analysis, and spatial transcriptomics allowed us to segregate the developing artery into spatially and functionally distinct subpopulations. In addition, expression of Cxcl12 suggests a morphogen gradient from arteries to capillaries, suggesting directed cell migration for pulmonary vascular development. Disruption of this gradient led to abnormal branching and pulmonary vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development.
2022-10-17 | GSE202132 | GEO
Project description:The formation of vascular structures is fundamental for in vitro tissue engineering. Vascularization can enable the nutrient supply within larger structures and increase transplantation efficiency, which are currently limiting factors in organoid research. We differentiated human induced pluripotent stem cells toward endothelial cells in 3D suspension culture. To investigate in vitro neovascularization and various 3D microenvironmental approaches, we designed a comprehensive single-cell transcriptomic study. Time-resolved single-cell transcriptomics of the endothelial and co-evolving mural cells gave insights into cell type development, stability, and plasticity. Transfer to a 3D hydrogel microenvironment induced neovascularization and facilitated tracing of sprouting, coalescing, and tubulogenic endothelial cells states. During maturation, we monitored two pericyte subtypes evolving of mural cells. Profiling cell-cell interactions between pericytes and endothelial cells confirmed in vivo angiogenic signaling and emphasized new cytokine signals during tubulogenesis. Our data, analyses, and results provide an in vitro roadmap to guide vascularization in future tissue engineering.
2022-03-08 | GSE196799 | GEO
Project description:To supply tumor tissues with nutrients and oxygen, endothelial progenitor cells (EPCs) are recruited to tumor bed and contribute to tumor neovascularization. HDAC7 is a critical regulator in EPC-mediated neovascularization. To explore the function of HDAC7 in neovascularization induced by EPCs, we use microarrays to profile the genes expression changes in HDAC7 lacking EPCs. HDAC7 silencing upregulated antiangiogenic genes transcription and suppressed proangiogenic genes expression, turning off the angiogenic switch for vessel formation.
2018-12-31 | GSE102178 | GEO
Project description:Apoptosis plays a pivotal role in embryogenesis and postnatal cell homeostasis, involving DNA or subcellular fragmentation, and shedding of small membranous microvesicles termed apoptotic bodies (AB). Following DNA damage, hypoxia, or vascular injury, the chemokine CXCL12 has been implicated in the recruitment of progenitor cells for tissue regeneration through its receptor CXCR4 and in mechanisms counteracting apoptosis. Whether AB deliver alarm signals for regenerative responses to neighbouring cells beyond recruitment or eat-me signals for phagocytes and relevance to diseases with abundant apoptosis, eg atherosclerosis, remains unknown. Here we show that endothelial cell-derived AB are generated during diet-induced atherosclerosis and can be transferred to recipient endothelial or smooth muscle cells to induce functional expression of CXCL12. This is mediated through miRNA-126 enriched in AB, which acts by silencing RGS16 translation and unlocking CXCR4 to unleash an auto-regulatory feedback loop inducing CXCL12. Injection of AB promoted mobilization and incorporation of progenitor cells, reducing diet-induced atherosclerosis in apolipoprotein E-deficient mice, and local transfer of microRNA-126 inhibited collar-induced arterial plaque formation. This was associated with increased smooth muscle content but decreased macrophage and apoptotic cell content, all features of plaque stability. Our data identify a new mechanism, by which AB confer microRNA-126 as a paracrine alarm messenger to enhance CXCR4 signals and CXCL12 expression, thereby limiting or repairing vascular damage. This adds to the important functions of microRNAs in health and disease and may extend to progenitor cell recruitment during other forms of tissue repair or homeostasis. AB were isolated from supernatants of apoptotic, serum-starved human umbilical vein endothelial cells (HUVECs) by sequential centrifugation steps. Total RNA was isolated from AB or HUVECs and microRNA was purified using the mirVanaTM miRNA Isolation Kit (Ambion). microRNA obtained from 10 µg of total RNA was labeled using the mirVanaTM miRNA Labeling Kit (Ambion) and fluorescent Cy3 (Molecular Probes), and hybridized to the Ambion mirVanaTM miRNA Bioarray (1566 v.1). Hybridized mirVana miRNA Bioarrays were scanned and quantified by using ImaGene 5.5.4 (Bio Discovery). Resulted signal intensities were background corrected and then normalized using variance stabilization normalization. (Huber, 2002).
2010-08-31 | E-GEOD-12696 | biostudies-arrayexpress
Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation, and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular (CAR) cells, leptin-receptor positive stromal cells, and nestin-GFP positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear if specific hematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (stromal-derived factor-1, SDF-1) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here, we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which includes CAR cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion in endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 in nestin-negative mesenchymal progenitors using Prx1-Cre is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence, and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B lymphoid progenitors and retains HPC in the bone marrow, while expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, support HSCs. Total of three samples of two groups analyzed. Replica samples of CXCL12-abundant reticular (CAR) cells from two CXCL12-GFP knock-in mice and a combined sample of PDGFRa+ Sca+ CD45- lineage- cells from three Prx1-Cre Rosa26Ai9/+ Cxcl12gfp/+ mice were used and analyzed.
2013-01-31 | E-GEOD-43613 | biostudies-arrayexpress
Project description:Apoptosis plays a pivotal role in embryogenesis and postnatal cell homeostasis, involving DNA or subcellular fragmentation, and shedding of small membranous microvesicles termed apoptotic bodies (AB). Following DNA damage, hypoxia, or vascular injury, the chemokine CXCL12 has been implicated in the recruitment of progenitor cells for tissue regeneration through its receptor CXCR4 and in mechanisms counteracting apoptosis. Whether AB deliver alarm signals for regenerative responses to neighbouring cells beyond recruitment or eat-me signals for phagocytes and relevance to diseases with abundant apoptosis, eg atherosclerosis, remains unknown. Here we show that endothelial cell-derived AB are generated during diet-induced atherosclerosis and can be transferred to recipient endothelial or smooth muscle cells to induce functional expression of CXCL12. This is mediated through miRNA-126 enriched in AB, which acts by silencing RGS16 translation and unlocking CXCR4 to unleash an auto-regulatory feedback loop inducing CXCL12. Injection of AB promoted mobilization and incorporation of progenitor cells, reducing diet-induced atherosclerosis in apolipoprotein E-deficient mice, and local transfer of microRNA-126 inhibited collar-induced arterial plaque formation. This was associated with increased smooth muscle content but decreased macrophage and apoptotic cell content, all features of plaque stability. Our data identify a new mechanism, by which AB confer microRNA-126 as a paracrine alarm messenger to enhance CXCR4 signals and CXCL12 expression, thereby limiting or repairing vascular damage. This adds to the important functions of microRNAs in health and disease and may extend to progenitor cell recruitment during other forms of tissue repair or homeostasis.
2010-08-31 | GSE12696 | GEO
Project description:We revealed the unique molecular signature characterizing CXCL12-deficient Cxcl12-GFP+ bone marrow stromal cells.
2020-10-27 | GSE160158 | GEO
Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation, and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular (CAR) cells, leptin-receptor positive stromal cells, and nestin-GFP positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear if specific hematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (stromal-derived factor-1, SDF-1) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here, we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which includes CAR cells and osteoblasts, results in constitutive HPC mobilization and a loss of B lymphoid progenitors, but HSC function is normal. Cxcl12 deletion in endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 in nestin-negative mesenchymal progenitors using Prx1-Cre is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence, and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B lymphoid progenitors and retains HPC in the bone marrow, while expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, support HSCs.
2013-01-31 | GSE43613 | GEO
Project description:Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAs/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76 gene signature DNA repair panel. Consistently, compared to Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. 5 different experimental conditions were compared (including GFP, PDGFB, PDGFB in conjunciton with Akt1, Akt2, or Akt3) with 3 mice per treatment
2015-02-24 | E-GEOD-66177 | biostudies-arrayexpress