Abstract
Introduction: A substantial number of studies in animal as well as human have shown contribution of bone marrow (BM) derived cells to postnatal angiogenesis in physiological and pathological conditions. Despite this information, questions remain regarding whether bone marrow-derived cells can become endothelial cells and engraft in blood vessels. Methods: To address this question, we generated chimeric rats containing BM from transgenic rat with the ubiquitin promoter driving GFP (GFP + BM) that was transplanted into a wild-type irradiated recipient. Chimeric rats were subjected to repetitive ischemia (RI, LAD occlusion) over a period of 17 days using a model in which the LAD is subjected to episodic ischemia to induce angiogenesis and collateral growth. Results: Measurements of myocardial blood flow (MBF) in the collateral-dependent region revealed a 3-fold increase in the ratio of collateral-dependent to normal zone MBF after 17 days. This increase in flow is due to collateral growth and angiogenesis in the ischemic region. Fluorescence microscopy in conjunction with immunostaining for rat endothelial cell antigen-1 showed the BM derived endothelial cells integrated into coronary blood vessels. We performed single cell RNAseq after sorting GFP + /propidium iodide - cells from hearts (enzymatic digestion) and bone marrow of control and RI rats. After quality filtering we had a total of 24103 cells. Clustering the cells identified 28 clusters. we annotated endothelial cell clusters based on the expression of endothelial cell markers. We had comparable proportion of endothelial cell populations in control and RI groups. Using canonical markers of different endothelial cell subtypes, we characterized arterial, venous, capillary, and lymphatic subpopulations within endothelial cell cluster. The endothelial cell population in the RI group had more angiogenic profile with higher expression of angiogenesis markers and vessel development pathways in gene ontology analysis. Conclusions: Taken together, our data suggest that BM cells can differentiate into endothelial cells in hearts, representing a heterogenous population of endothelial cells and contributing to vascular growth.
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