Aicher Alexandra, Rentsch Markus, Sasaki Ken-ichiro, Ellwart Joachim W, Fändrich Fred, Siebert Reiner, Cooke John P, Dimmeler Stefanie, Heeschen Christopher
Department of Molecular Cardiology, J.W. Goethe University, Frankfurt, Germany.
Circ Res. 2007 Mar 2;100(4):581-9. doi: 10.1161/01.RES.0000259562.63718.35. Epub 2007 Feb 1.
Circulating progenitor cells home to sites of postnatal neovascularization and differentiate into endothelial cells but questions remain regarding the source of these cells. Indeed, a recent study suggests that nonbone marrow-derived cells may be even more important than bone marrow-derived cells in the setting of transplant arteriosclerosis. Thus, we aimed to thoroughly investigate the contribution of nonbone marrow-derived progenitor cells for neovascularization. We exclusively identified nonbone marrow-derived progenitor cells by combining a parabiosis model with reverse bone marrow transplantation followed by hindlimb ischemia. In this model, nonbone marrow-derived circulating progenitor cells attributed for 74+/-13% of the circulating progenitor cells that incorporated into the ischemic hindlimb. Increasing evidence suggests that organs such as small intestine and liver contain a considerable number of tissue resident progenitor cells and, thus, represent putative sources for nonbone marrow-derived progenitors. To track organ-derived progenitors, we transplanted sex-mismatched small intestine or liver, respectively, into rats followed by induction of hindlimb ischemia. These experiments show that organ-derived progenitor cells are contributing to postnatal vasculogenesis (intestine: 4.7+/-3.7%; liver: 6.3+/-2.2%). Based on the subsequent observation that liver-derived nonhematopoietic c-kit(+)CD45(-) progenitors are mobilized on induction of hindlimb ischemia, we prospectively isolated and intravenously infused these progenitors from murine livers. The isolated cells demonstrated a marked capacity for enhancing neovascularization and restoring blood flow to the ischemic hindlimb (no cells: 26.4+/-4.8% of normal blood flow; c-kit(+)CD45(-) cells: 67.0+/-8.0% of normal flow; P<0.01). In conclusion, we find that nonbone marrow-derived c-kit(+)CD45(-) progenitors contribute to postnatal neovascularization to an extent that is similar to that of bone marrow-derived progenitor cells. Intestine and liver represent a rich source for mobilized tissue-residing progenitor cells.
循环祖细胞归巢至出生后新生血管形成的部位并分化为内皮细胞，但这些细胞的来源仍存在疑问。事实上，最近一项研究表明，在移植性动脉硬化的情况下，非骨髓来源的细胞可能比骨髓来源的细胞更为重要。因此，我们旨在全面研究非骨髓来源的祖细胞对新生血管形成的贡献。我们通过将联体共生模型与反向骨髓移植相结合，随后进行后肢缺血，专门鉴定了非骨髓来源的祖细胞。在这个模型中，非骨髓来源的循环祖细胞占整合到缺血后肢的循环祖细胞的74±13%。越来越多的证据表明，小肠和肝脏等器官含有大量组织驻留祖细胞，因此是非骨髓来源祖细胞的潜在来源。为了追踪器官来源的祖细胞，我们分别将性别不匹配的小肠或肝脏移植到大鼠体内，随后诱导后肢缺血。这些实验表明，器官来源的祖细胞对出生后血管生成有贡献（小肠：4.7±3.7%；肝脏：6.3±2.2%）。基于随后的观察结果，即肝脏来源的非造血c-kit(+)CD45(-)祖细胞在诱导后肢缺血时被动员，我们从鼠肝脏中前瞻性地分离并静脉注射了这些祖细胞。分离出的细胞显示出显著的增强新生血管形成和恢复缺血后肢血流的能力（无细胞：正常血流的26.4±4.8%；c-kit(+)CD45(-)细胞：正常血流的67.0±8.0%；P<0.01）。总之，我们发现非骨髓来源的c-kit(+)CD45(-)祖细胞对出生后新生血管形成的贡献程度与骨髓来源的祖细胞相似。小肠和肝脏是动员的组织驻留祖细胞的丰富来源。
