Capla Jennifer M, Grogan Raymon H, Callaghan Matthew J, Galiano Robert D, Tepper Oren M, Ceradini Daniel J, Gurtner Geoffrey C
New York, N.Y.; and Stanford, Calif. From the Laboratory of Microvascular Research and Vascular Tissue Engineering, Institute of Reconstructive Plastic Surgery, New York University Medical Center; and Department of Surgery, Stanford University.
Plast Reconstr Surg. 2007 Jan;119(1):59-70. doi: 10.1097/01.prs.0000244830.16906.3f.
Diabetics suffer from vascular dysfunction with increased risks of coronary artery disease and peripheral vascular disease secondary to an impaired ability to respond to tissue ischemia. Because endothelial progenitor cells are known to home to sites of ischemia and participate in new blood vessel growth, the authors examined the effects of diabetes on human endothelial progenitor cell function and peripheral tissue signaling in hypoxia, and determined whether these cells might be a useful cell-based therapy for diabetic vascular complications.
Circulating human endothelial progenitor cells from type 2 diabetic patients and controls were isolated and subjected to in vitro adhesion, migration, and proliferation assays (n = 5). Cell mobilization and recruitment were studied in vivo in diabetic and nondiabetic environments (n = 6). Exogenous human diabetic and normal cells were analyzed for therapeutic efficacy in a murine ischemia model (n = 6).
Adhesion, migration, and proliferation of human diabetic endothelial progenitor cells in response to hypoxia was significantly reduced compared with controls. In diabetic mice, cell mobilization from the bone marrow and recruitment into ischemic tissue was significantly reduced compared with controls. Normal cells injected systemically as replacement therapy in a diabetic mouse increased but did not normalize ischemic tissue survival.
These findings suggest that diabetes causes defects in both the endothelial progenitor cell and peripheral tissue responses to hypoxia. These changes in endothelial progenitor cell function and signaling offer a novel explanation for the poor clinical outcome of type 2 diabetics following ischemic events. Based on these findings, it is unlikely that endothelial progenitor cell-based cellular therapies will be able to prevent diabetic complications.
糖尿病患者存在血管功能障碍，继发于对组织缺血反应能力受损，患冠状动脉疾病和外周血管疾病的风险增加。由于已知内皮祖细胞会归巢至缺血部位并参与新血管生成，作者研究了糖尿病对人内皮祖细胞在缺氧状态下功能及外周组织信号传导的影响，并确定这些细胞是否可能成为治疗糖尿病血管并发症的有效细胞疗法。
分离2型糖尿病患者和对照组的循环人内皮祖细胞，并进行体外黏附、迁移和增殖分析（n = 5）。在糖尿病和非糖尿病环境下对细胞动员和募集进行体内研究（n = 6）。分析外源性人糖尿病细胞和正常细胞在小鼠缺血模型中的治疗效果（n = 6）。
与对照组相比，人糖尿病内皮祖细胞在缺氧状态下的黏附、迁移和增殖显著降低。在糖尿病小鼠中，与对照组相比，骨髓细胞动员及向缺血组织的募集显著减少。作为替代疗法全身注射正常细胞可增加糖尿病小鼠缺血组织的存活，但未使其恢复正常。
这些发现表明，糖尿病会导致内皮祖细胞及外周组织对缺氧的反应出现缺陷。内皮祖细胞功能和信号传导的这些变化为2型糖尿病患者缺血事件后不良临床结局提供了新的解释。基于这些发现，基于内皮祖细胞的细胞疗法不太可能预防糖尿病并发症。
