Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization
Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization
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DOI：
10.1161/01.res.85.3.221
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发表时间：
1999-08-06
影响因子：
20.1
通讯作者：
Isner, JM
中科院分区：
文献类型：
--
作者：
Asahara, T;Masuda, H;Isner, JM
循环内皮祖细胞（EPC）已在成年物种的外周血中分离出来。为了确定EPCs对出生后血管生成的起源和作用，在内皮细胞特异性启动子（Flk-1/LZ或Tie-2/LZ）的转录调控下组成型表达β-半乳糖苷酶的转基因小鼠被用作移植供体。诱导排卵后，在黄体和子宫内膜新血管系统中鉴定出由 flk-1 或 tie-2/lacZ 融合转录本指示的 EPC 定位。将小鼠同系结肠癌细胞（MCA38）皮下植入Flk-1/LZ/BMT（骨髓移植）和Tie-2/LZ/BMT小鼠中； 1周时收获的肿瘤样本显示出丰富的flk-1/lacZ和tie-2/lacZ融合转录物，并且用X-gal染色的切片表明，正在发育的肿瘤的新血管系统经常包含表达Flk-1或Tie-2的EPC。在皮肤去除后4天和7天通过穿刺活检检查的皮肤伤口显示EPC以高频率掺入新血管形成灶中。后肢缺血发生一周后，发现 lacZ 阳性 EPC 掺入骨骼肌细胞的毛细血管中。永久结扎左冠状动脉前降支后，心肌梗塞部位的组织学样本显示，EPC 并入梗塞边界处的新血管形成灶中。这些发现表明，出生后的新血管形成并不完全依赖于先前存在的血管的萌芽（血管生成）；相反，EPCs从骨髓循环并融入并因此促进出生后生理和病理性新生血管形成，这与出生后血管发生一致。
Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing beta-galactosidase under the transcriptional regulation of an endothelial cell-specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1- or Tie-2-expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch biopsy disclosed EPCs incorporated into foci of neovascularization at high frequency. One week after the onset of hindlimb ischemia, lacZ-positive EPCs were identified incorporated into capillaries among skeletal myocytes. After permanent ligation of the left anterior descending coronary artery, histological samples from sites of myocardial infarction demonstrated incorporation of EPCs into foci of neovascularization at the border of the infarct. These findings indicate that postnatal neovascularization does not rely exclusively on sprouting from preexisting blood vessels (angiogenesis); instead, EPCs circulate from bone marrow to incorporate into and thus contribute to postnatal physiological and pathological neovascularization, which is consistent with postnatal vasculogenesis.