Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Stem Cells. 2013 Feb;31(2):305-16. doi: 10.1002/stem.1285.
Human microvascular pericytes (CD146(+)/34(-)/45(-)/56(-)) contain multipotent precursors and repair/regenerate defective tissues, notably skeletal muscle. However, their ability to repair the ischemic heart remains unknown. We investigated the therapeutic potential of human pericytes, purified from skeletal muscle, for treating ischemic heart disease and mediating associated repair mechanisms in mice. Echocardiography revealed that pericyte transplantation attenuated left ventricular dilatation and significantly improved cardiac contractility, superior to CD56+ myogenic progenitor transplantation, in acutely infarcted mouse hearts. Pericyte treatment substantially reduced myocardial fibrosis and significantly diminished infiltration of host inflammatory cells at the infarct site. Hypoxic pericyte-conditioned medium suppressed murine fibroblast proliferation and inhibited macrophage proliferation in vitro. High expression by pericytes of immunoregulatory molecules, including interleukin-6, leukemia inhibitory factor, cyclooxygenase-2, and heme oxygenase-1, was sustained under hypoxia, except for monocyte chemotactic protein-1. Host angiogenesis was significantly increased. Pericytes supported microvascular structures in vivo and formed capillary-like networks with/without endothelial cells in three-dimensional cocultures. Under hypoxia, pericytes dramatically increased expression of vascular endothelial growth factor-A, platelet-derived growth factor-β, transforming growth factor-β1 and corresponding receptors while expression of basic fibroblast growth factor, hepatocyte growth factor, epidermal growth factor, and angiopoietin-1 was repressed. The capacity of pericytes to differentiate into and/or fuse with cardiac cells was revealed by green fluorescence protein labeling, although to a minor extent. In conclusion, intramyocardial transplantation of purified human pericytes promotes functional and structural recovery, attributable to multiple mechanisms involving paracrine effects and cellular interactions.
人微血管周细胞（CD146(+)/34(-)/45(-)/56(-)）含有多能前体细胞，可修复/再生有缺陷的组织，特别是骨骼肌。然而，它们修复缺血心脏的能力尚不清楚。我们研究了从骨骼肌中纯化的人周细胞在治疗缺血性心脏病和介导相关修复机制方面的治疗潜力。在急性心肌梗死的小鼠心脏中，超声心动图显示周细胞移植可减轻左心室扩张，并显著改善心脏收缩功能，优于 CD56+ 成肌祖细胞移植。周细胞治疗可显著减少心肌纤维化，并显著减少梗死部位宿主炎症细胞的浸润。缺氧周细胞条件培养基可抑制小鼠成纤维细胞增殖，并在体外抑制巨噬细胞增殖。周细胞高表达免疫调节分子，包括白细胞介素-6、白血病抑制因子、环氧化酶-2 和血红素加氧酶-1，但单核细胞趋化蛋白-1除外。宿主血管生成显著增加。周细胞在体内支持微血管结构，并在三维共培养中与/无内皮细胞形成毛细血管样网络。在缺氧条件下，周细胞显著增加血管内皮生长因子-A、血小板衍生生长因子-β、转化生长因子-β1 及其相应受体的表达，而碱性成纤维细胞生长因子、肝细胞生长因子、表皮生长因子和血管生成素-1 的表达受到抑制。通过绿色荧光蛋白标记显示，周细胞具有向心肌细胞分化和/或融合的能力，尽管程度较小。总之，纯化的人周细胞的心肌内移植可促进功能和结构的恢复，这归因于涉及旁分泌作用和细胞相互作用的多种机制。
