Enhancing Retention of Mesenchymal Stem Cells with Prosurvival Factors Promotes Angiogenesis in a Mouse Model of Limb Ischemia
Enhancing Retention of Mesenchymal Stem Cells with Prosurvival Factors Promotes Angiogenesis in a Mouse Model of Limb Ischemia
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DOI：
10.1089/scd.2018.0090
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发表时间：
2018-12-18
影响因子：
4
通讯作者：
Zhou, Ping
中科院分区：
文献类型：
--
作者：
Cortez-Toledo, Elizabeth;Rose, Melanie;Zhou, Ping
间充质干细胞/基质细胞（MSC）在治疗缺血性损伤，包括中风，心肌梗死和肢体缺血方面提供了很大的希望。然而，移植后细胞存活率差仍然是实现有效MSC疗法的主要障碍。为了提高细胞的存活率和保留率，我们在诱导后肢缺血后，将含有或不含特定促生存因子（PSF）的混合物（由IGF 1、Bcl-X-L、半胱天冬酶抑制剂、线粒体途径抑制剂和Matrigel组成）的人骨髓MSC移植到免疫缺陷小鼠的肢体中。生物发光成像显示，PSF显著延长了骨髓间充质干细胞在缺血肢体肌肉中的滞留。移植后9周，使用显微计算机断层扫描对小鼠肢体肌肉血管进行成像，我们发现，与非移植对照小鼠相比，移植无PSF的MSC的小鼠缺血肢体血管没有显着增加。相比之下，与未接受MSC的对照小鼠相比，移植MSC加PSF的小鼠在缺血肢体中的血管，特别是较大和分支血管显着增加。因此，我们证明了使用PSF的MSC的长期保留有效地促进缺血动物肢体中的血管生成。这项研究强调了提高细胞存活率在开发有效的MSC疗法治疗血管疾病中的重要性。
Mesenchymal stem/stromal cells (MSCs) offer great promise in the treatment of ischemic injuries, including stroke, heart infarction, and limb ischemia. However, poor cell survival after transplantation remains a major obstacle to achieve effective MSC therapies. To improve cell survival and retention, we transplanted human bone marrow MSCs with or without a specific prosurvival factor (PSF) cocktail consisting of IGF1, Bcl-X-L, a caspase inhibitor, a mitochondrial pathway inhibitor, and Matrigel into the limbs of immune deficient mice, after induction of hindlimb ischemia. The PSF markedly prolonged the retention of the MSCs in the ischemic limb muscles as demonstrated by bioluminescence imaging. Using microcomputed tomography to image the limb muscle vasculature in the mice 9 weeks after the transplantation, we found that the mice transplanted with MSCs without PSF did not show a significant increase in the blood vessels in the ischemic limb compared with the nontransplanted control mice. In contrast, the mice transplanted with MSCs plus PSF showed a significant increase in the blood vessels, especially the larger and branching vessels, in the ischemic limb compared with the control mice that did not receive MSCs. Thus, we demonstrated that prolonged retention of MSCs using PSF effectively promoted angiogenesis in ischemic animal limbs. This study highlights the importance of enhancing cell survival in the development of effective MSC therapies to treat vascular diseases.