Identification of a coronary vascular progenitor cell in the human heart (Retracted Article)
Identification of a coronary vascular progenitor cell in the human heart (Retracted Article)
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DOI：
10.1073/pnas.0907622106
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发表时间：
2009-09-15
影响因子：
11.1
通讯作者：
Anversa, Piero
中科院分区：
文献类型：
--
作者：
Bearzi, Claudia;Leri, Annarosa;Anversa, Piero
在受损的心肌中，能够产生小阻力小动脉和毛细血管结构的原始细胞已经被反复鉴定。然而，这些细胞并不能形成大的传导冠状动脉，这对缺血性心脏的治疗有重要意义。在目前的研究中，我们确定了人类心脏是否拥有一类调节内皮细胞(ECs)和平滑肌细胞(SMC)的生长和血管生成的前体细胞。利用血管内皮生长因子受体2(KDR)的表达，结合干细胞抗原c-Kit，从人心肌标本中分离和扩增出一株常驻冠脉血管前体细胞(VPC)。在结构上，在冠脉血管壁内发现了由c-kit-KDR阳性的血管内皮细胞组成的血管壁龛。VPC通过缝隙连接连接到作为支持细胞的ECs、SMC和成纤维细胞。在体外，VPC具有自我更新和克隆形成能力，主要分化为ECs和SMC，部分分化为心肌细胞。为了建立VPC的功能性导入，在免疫抑制的狗身上制造了一个严重的狭窄，并在狭窄的动脉附近注射标记的人VPC。1个月后，狭窄动脉远端的冠脉血流量(CBF)增加，导致缺血心肌功能改善。发现了再生的大、中、小冠状动脉和毛细血管。综上所述，人类心脏包含一个VPC池，可以在临床上实施，以形成功能正常的冠状动脉血管，并改善缺血性心肌病患者的CBF。
Primitive cells capable of generating small resistance arterioles and capillary structures in the injured myocardium have been identified repeatedly. However, these cells do not form large conductive coronary arteries that would have important implications in the management of the ischemic heart. In the current study, we determined whether the human heart possesses a class of progenitor cells that regulates the growth of endothelial cells (ECs) and smooth muscle cells (SMCs) and vasculogenesis. The expression of vascular endothelial growth-factor receptor 2 (KDR) was used, together with the stem cell antigen c-kit, to isolate and expand a resident coronary vascular progenitor cell (VPC) from human myocardial samples. Structurally, vascular niches composed of c-kit-KDR-positive VPCs were identified within the walls of coronary vessels. The VPCs were connected by gap junctions to ECs, SMCs, and fibroblasts that operate as supporting cells. In vitro, VPCs were self-renewing and clonogenic and differentiated predominantly into ECs and SMCs and partly into cardiomyocytes. To establish the functional import of VPCs, a critical stenosis was created in immunosuppressed dogs, and tagged human VPCs were injected in proximity to the constricted artery. One month later, there was an increase in coronary blood flow (CBF) distal to the stenotic artery, resulting in functional improvement of the ischemic myocardium. Regenerated large, intermediate, and small human coronary arteries and capillaries were found. In conclusion, the human heart contains a pool of VPCs that can be implemented clinically to form functionally competent coronary vessels and improve CBF in patients with ischemic cardiomyopathy.