The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair
The Wnt modulator sFRP2 enhances mesenchymal stem cell engraftment, granulation tissue formation and myocardial repair
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DOI：
10.1073/pnas.0803437105
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发表时间：
2008-11-25
影响因子：
11.1
通讯作者：
Young, Pampee P.
中科院分区：
文献类型：
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作者：
Alfaro, Maria P.;Pagni, Matthew;Young, Pampee P.
使用多能间充质干细胞(MSCs)进行器官再生的基于细胞的疗法正在被用于心脏病、骨科损伤和生物材料制造。然而，调控MSC介导的再生或增强其治疗效果的分子途径却知之甚少。我们比较了从MRL/MPJ小鼠分离的MSCs和从C57BL/6(WT)小鼠分离的MSCs，已知这些细胞具有增强的再生能力。与WT-MSCs相比，MRL-MSCs在小鼠修复刺激模型中表现出更多的增殖、体内植入、实验性肉芽组织重建和组织血管形成。在小鼠心肌梗死模型中，与WT-MSCs相比，MRL-MSCs还缩小了梗死范围并改善了功能。基因组和功能分析表明，在MRL-MSCs中，典型的WRIT途径下调，其特征是特定分泌的卷曲相关蛋白(SFRP)显着上调。在MRL-MSCs中，shRNA特异性下调SFRP2基因，可降低MRL-MSC诱导的实验性肉芽组织中SFRP2的增殖、植入和血管密度。这些结果导致我们通过逆转录病毒转导产生了高表达SFRP2的WT-MSCs(SFRP2-MSCs)。SFRP2-MSCs在体外保持其多向分化的能力，当植入体内时，重现了MRL表型。心肌梗死周围注射SFRP2-MSCs后，心肌损伤后植入增加，血管密度增加，梗死范围缩小，心功能增强。这些发现表明，SFRP2是MSCs中优势再生表型的生物发生的关键分子。
Cell-based therapies, using multipotent mesenchymal stem cells (MSCs) for organ regeneration, are being pursued for cardiac disease, orthopedic injuries and biomaterial fabrication. The molecular pathways that regulate MSC-mediated regeneration or enhance their therapeutic efficacy are, however, poorly understood. We compared MSCs isolated from MRL/MpJ mice, known to demonstrate enhanced regenerative capacity, to those from C57BL/6 (WT) mice. Compared with WT-MSCs, MRL-MSCs demonstrated increased proliferation, in vivo engraftment, experimental granulation tissue reconstitution, and tissue vascularity in a murine model of repair stimulation. The MRL-MSCs also reduced infarct size and improved function in a murine myocardial infarct model compared with WT-MSCs. Genomic and functional analysis indicated a downregulation of the canonical Writ pathway in MRL-MSCs characterized by significant up-regulation of specific secreted frizzled-related proteins (sFRPs). Specific knockdown of sFRP2 by shRNA in MRL-MSCs decreased their proliferation and their engraftment in and the vascular density of MRL-MSC-generated experimental granulation tissue. These results led us to generate WT-MSCs overexpressing sFRP2 (sFRP2-MSCs) by retroviral transduction. sFRP2-MSCs maintained their ability for multilineage differentiation in vitro and, when implanted in vivo, recapitulated the MRL phenotype. Peri-infarct intramyocardial injection of sFRP2-MSCs resulted in enhanced engraftment, vascular density, reduced infarct size, and increased cardiac function after myocardial injury in mice. These findings implicate sFRP2 as a key molecule for the biogenesis of a superior regenerative phenotype in MSCs.