Institut National de la Santé et de la Recherche Médicale U.689, Cardiovascular Research Center Lariboisière, Hôpital Lariboisière, et Université Paris 7, F-75010 Paris, France.
Stem Cells. 2009 Nov;27(11):2712-21. doi: 10.1002/stem.219.
Angiogenic cell therapy with the transplantation of endothelial progenitor cells (EPC) or bone marrow mononuclear cells (BM-MNC) receives considerable attention as an approach to revascularize ischemic tissues. Adiponectin is a circulating hormone produced by the apM1 gene in adipocytes. Adiponectin modulates lipid metabolism and obesity, and it was recently found to promote physiological angiogenesis in response to ischemia. Patients with multiple cardiovascular disease risk factors or myocardial infarction may benefit from progenitor cell therapy, but they display depressed adiponectinemia. We hypothesized that adiponectin stimulation of transplanted cells is critical for their pro-angiogenic function. We aimed to establish whether adiponectinemia in the cell donor or in the cell recipient determines the success of pro-angiogenic cell therapy. In vitro, we found that conditioned media derived from wild-type adipocytes (adipo-CM) or purified adiponectin strongly enhanced BM-MNC survival and proliferation and stimulated EPC differentiation, whereas adipo-CM from apM1-/- adipocytes was one-half less effective. On the other hand, wild-type and apM1-/- BM-MNC displayed similar resistance to apoptosis and proliferation rates. In vivo, wild-type, and apM1-/- BM-MNC induced similar angiogenic reactions in wild-type ischemic hindlimbs. In contrast, wild-type BM-MNC had much diminished effects in apM1-/- ischemic hindlimbs. We concluded that adiponectin enhances BM-MNC survival and proliferation, and adiponectinemia in the cell therapy recipient is essential for the pro-angiogenic benefits of cell therapy. These observations imply that progenitor cell transplantation might only induce angiogenesis in patients with high adiponectinemia.
血管生成细胞治疗，通过移植内皮祖细胞（EPC）或骨髓单个核细胞（BM-MNC），作为一种使缺血组织再血管化的方法受到了广泛关注。脂联素是一种由脂肪细胞中的 apM1 基因产生的循环激素。脂联素调节脂质代谢和肥胖，最近发现它能促进生理性血管生成以应对缺血。患有多种心血管疾病危险因素或心肌梗死的患者可能受益于祖细胞治疗，但他们表现出脂联素血症降低。我们假设，移植细胞的脂联素刺激对于其促血管生成功能至关重要。我们旨在确定供体细胞或受体细胞中的脂联素血症是否决定促血管生成细胞治疗的成功。在体外，我们发现野生型脂肪细胞（adipo-CM）或纯化脂联素的条件培养基强烈增强了 BM-MNC 的存活和增殖，并刺激了 EPC 分化，而 apM1-/-脂肪细胞的 adipo-CM 则只有一半的效果。另一方面，野生型和 apM1-/-BM-MNC 对细胞凋亡和增殖率的抵抗力相似。在体内，野生型和 apM1-/-BM-MNC 在野生型缺血后肢中诱导相似的血管生成反应。相比之下，野生型 BM-MNC 在 apM1-/-缺血后肢中的作用大大减弱。我们得出的结论是，脂联素增强了 BM-MNC 的存活和增殖，而细胞治疗受者中的脂联素血症对于细胞治疗的促血管生成益处至关重要。这些观察结果表明，祖细胞移植可能仅在高脂联素血症患者中诱导血管生成。
