Differential activity of bone marrow hematopoietic stem cell subpopulations for EPC development and ischemic neovascularization |
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Authors: | Kwon Sang-Mo Lee Yun-Kyung Yokoyama Ayumi Jung Seok-Yun Masuda Haruchika Kawamoto Atsuhiko Lee You Mie Asahara Takayuki |
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Affiliation: | a Laboratory for Vascular Medicine & Stem Cell Biology, Department of Physiology, School of Medicine, Pusan National University, Yangsan, South Koreab College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Koreac Vascular Regeneration Research Group, Institute of Biomedical Research and Innovation, Kobe, Japand Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan |
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Abstract: | Although endothelial progenitor cells (EPCs) differentiate from minor populations of stem cells in bone marrow (BM), the differential role of hematopoietic stem cell (HSC) subpopulations in EPC development is largely unclear. Morphological characterization of EPC colonies has revealed that c-kit+/Sca-1+/lineage (Lin)-(KSL) cells mainly develop small EPC-colony forming units (CFUs) not large EPC-CFUs. In contrast, c-kit+/Sca-1−/Lin− (KL) cells develop large EPC-CFUs not small EPC-CFUs. Neither c-kit-/Sca-1+/Lin− (SL) cells nor c-kit−/Sca-1−/Lin− (L) cells develop EPC-CFUs to an appreciable extent. Hindlimb ischemia enhances formation of large EPC-CFUs from all HSC subpopulations, suggesting an important role for ischemia in functional EPC development. Real time RT-PCR analysis shows that KSL, KL and SL cells but not L cells express various factors at high levels, maintaining a BM-EPC pool. In hindlimb ischemia, transplanted KSL, KL and SL cells efficiently differentiate into endothelial lineage cells in situ and augment capillary density. The percentage of Ki-67+ cycling cells among transplanted cells in ischemic tissue was also greater for KSL, KL and SL cells than L cells. Moreover, the frequency of VEGF- or SDF-1-expressing cells was higher transplanted KSL, KL or SL cells than L cells. Thus, KSL, KL and SL cells are not different in their angiogenic competence under ischemic conditions. In conclusion, although KSL cells are clearly the most potent contributors to EPC development, KL and SL cells may also contribute to neovascularization via both autocrine and paracrine mechanisms in response to ischemic signals. |
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Keywords: | Adult stem cells Angiogenesis Endothelial progenitor cells Vascular repair Hematopoietic stem cell subpopulations c-kit Sca-1 |
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