Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms.
Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms.
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DOI：
10.1161/circresaha.113.301202
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发表时间：
2013-08-16
影响因子：
20.1
通讯作者：
Houser SR
中科院分区：
文献类型：
--
作者：
Duran JM;Makarewich CA;Sharp TE;Starosta T;Zhu F;Hoffman NE;Chiba Y;Madesh M;Berretta RM;Kubo H;Houser SR
自体骨髓或心脏源性干细胞治疗心脏病已在临床试验中证明了安全性和有效性，但功能改善有限。找到最适合心脏再生的最佳干细胞类型是改善临床结果的关键。确定新型骨源性干细胞支持受损心脏的机制。从EGFP+转基因小鼠中分离皮质骨干细胞（CBSC）和心脏源性干细胞（CDC），并显示其表达c-kit和Sca-1以及参与心脏保护、血管生成和干细胞功能的8种旁分泌因子。野生型C57 BL/6小鼠进行假手术（n=21）或注射CBSC（n=67）、CDC（n=36）或盐水（n=60）的心肌梗死（MI）。使用超声心动图监测心脏功能。只有2/8的旁分泌因子在体内的EGFP+ CBSCs中检测到（碱性成纤维细胞生长因子和血管内皮生长因子），这种表达与梗死边缘区的新血管形成增加有关。与CDC或生理盐水治疗的MI对照组相比，CBSC治疗改善了存活率、心脏功能、局部应变、减弱了重构，并减少了梗死面积。6周时，EGFP+心肌细胞，血管平滑肌和内皮细胞可以在CBSC中识别，但在CDC治疗的动物中没有。EGFP+ CBSC衍生的分离的肌细胞更小并且更频繁地是单核的，但是在功能上与EGFP-肌细胞不可区分。CBSC通过两种机制改善存活率、心脏功能并减弱重塑：1）刺激内源性新血管形成的促血管生成因子的分泌，以及2）分化成功能性成体肌细胞和血管细胞。
Autologous bone marrow- or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is key toward improving clinical outcomes. To determine the mechanism by which novel bone-derived stem cells support the injured heart. Cortical bone stem cells (CBSCs) and cardiac-derived stem cells (CDCs) were isolated from EGFP+ transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction (MI) with injection of CBSCs (n=67), CDCs (n=36) or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to CDC- or saline-treated MI controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle and endothelial cells could be identified in CBSC- but not in CDC-treated animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP- myocytes. CBSCs improve survival, cardiac function, and attenuate remodeling through two mechanisms:1) secretion of pro-angiogenic factors that stimulate endogenous neovascularization, and 2) differentiation into functional adult myocytes and vascular cells.