Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways.
Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways.
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DOI：
10.1161/circresaha.116.309281
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发表时间：
2016-09-30
影响因子：
20.1
通讯作者：
Hare JM
中科院分区：
文献类型：
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作者：
Hatzistergos KE;Saur D;Seidler B;Balkan W;Breton M;Valasaki K;Takeuchi LM;Landin AM;Khan A;Hare JM
来自表达细胞表面受体cKit的心脏组织的培养扩增细胞正在进行临床试验，作为心力衰竭和先天性心脏病的细胞来源。虽然越来越多的数据支持间充质干细胞（MSC）增强心脏cKit+细胞（CSC）的功效，但这种协同效应的潜在机制仍不完全清楚。为了验证MSC通过SDF 1/CXCR 4和SCF/cKit途径刺激内源性CSC增殖、迁移和分化的假设。使用遗传谱系追踪方法，我们发现，在出生后的小鼠心脏，cKit+细胞增殖，迁移，并形成心肌细胞，但不是内皮细胞。CSC表现出显着的趋化性和增殖反应时，共培养与MSC，但不是心脏基质细胞。AMD 3100对CXCR 4通路的拮抗作用抑制了MSC诱导的CSC趋化性，但刺激了CSC心肌形成（p<0.0001）。此外，MSC通过SCF/cKit和SDF 1/CXCR 4途径增强CSC增殖（p<0.0001）。总之，这些发现表明MSC对CSC迁移、增殖和分化表现出深刻而不同的作用，并表明与使用CSC和MSC的组合疗法相关的改善的心脏再生的潜在机制。这些发现对采用CSC和MSC混合物的基于细胞的治疗策略具有重要的治疗意义。
Culture expanded cells originating from cardiac tissue that express the cell surface receptor cKit are undergoing clinical testing as a cell source for heart failure and congenital heart disease. While accumulating data support that mesenchymal stem cells (MSCs) enhance the efficacy of cardiac cKit+ cells (CSCs), the underlying mechanism for this synergistic effect remain incompletely understood. To test the hypothesis that MSCs stimulate endogenous CSCs to proliferate, migrate, and differentiate via the SDF1/CXCR4 and SCF/cKit pathways. Using genetic lineage-tracing approaches we show that in the postnatal murine heart, cKit+ cells proliferate, migrate, and form cardiomyocytes, but not endothelial cells. CSCs exhibit marked chemotactic and proliferative responses when co-cultured with MSCs but not cardiac stromal cells. Antagonism of the CXCR4 pathway with AMD3100 inhibited MSC-induced CSC chemotaxis but stimulated CSC cardiomyogenesis (p<0.0001). Furthermore, MSCs enhanced CSC proliferation via the SCF/cKit and SDF1/CXCR4 pathways (p<0.0001). Together these findings show that MSCs exhibit profound, yet differential, effects upon CSC migration, proliferation and differentiation, and suggest a mechanism underlying the improved cardiac regeneration associated with combination therapy using CSCs and MSCs. These findings have important therapeutic implications for cell-based therapy strategies that employ mixtures of CSCs and MSCs.