| Abstract: |
BACKGROUND: Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. METHODS: We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of Abcg2-expressing ECs to vessel development and regeneration, we developed Abcg2CreErt2;ROSA TdTomato mice and performed lineage tracing during mouse development and during tissue regeneration after myocardial infarction injury. RNA sequencing and chromatin methylation chromatin immunoprecipitation followed by sequencing were conducted to study the gene regulation in Abcg2-expressing ECs. RESULTS: In human and mouse vessels, ECs with higher ABCG2 expression (ABCECs) possess higher clonal proliferative potential and in vivo vessel-forming potential compared with mature ECs. These cells could clonally contribute to vessel formation in primary and secondary recipients after transplantation. These features of ABCECs meet the criteria of CRECs. Results from lineage tracing experiments confirm that Abcg2-expressing CRECs (AbcCRECs) contribute to arteries, veins, and capillaries in cardiac tissue development and vascular tissue regeneration after myocardial infarction. Transcriptome and epigenetic analyses reveal that a gene expression signature involved in angiogenesis and vessel development is enriched in AbcCRECs. In addition, various angiogenic genes, such as Notch2 and Hey2, are bivalently modified by trimethylation at the 4th and 27th lysine residue of histone H3 (H3K4me3 and H3K27me3) in AbcCRECs. CONCLUSIONS: These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction. © 2024 American Heart Association, Inc. |
| Keywords: |
vasculotropin; adult; unclassified drug; human cell; genetics; nonhuman; flow cytometry; cell proliferation; mouse; phenotype; animal; cytology; metabolism; animals; mice; cd34 antigen; gene expression; differential diagnosis; neoplasm proteins; notch receptor; developmental biology; tissue regeneration; pathology; angiogenesis; cell lineage; transgenic mouse; mice, transgenic; collagen type 1; endothelium cell; endothelial cells; regeneration; epigenetics; histone; chromatin immunoprecipitation; heart infarction; histone h3; tumor protein; breast cancer resistance protein; abcg2 protein, human; blood vessel; tamoxifen; down regulation; transcription factor pax6; neovascularization, physiologic; octamer transcription factor 4; transcription factor sox2; therapy; transcription factor nfat; myocardial infarction; blood vessels; transcription factor nanog; endothelial leukocyte adhesion molecule 1; calretinin; rna sequence; canonical wnt signaling; notch2 receptor; colony formation; histone modification; human umbilical vein endothelial cells; cell self-renewal; umbilical vein endothelial cell; humans; human; article; receptor type tyrosine protein phosphatase c; platelet endothelial cell adhesion molecule 1; atp binding cassette transporter, subfamily g, member 2; abc transporter subfamily g; atp binding cassette subfamily g member 2; hairy enhancer of split related with yrpw motif protein 2; abcg2 protein, mouse
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