Hypoxia Preconditioned Mesenchymal Stem Cells Improve Vascular and Skeletal Muscle Fiber Regeneration After Ischemia Through a Wnt4-dependent Pathway
Hypoxia Preconditioned Mesenchymal Stem Cells Improve Vascular and Skeletal Muscle Fiber Regeneration After Ischemia Through a Wnt4-dependent Pathway
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DOI：
10.1038/mt.2010.108
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发表时间：
2010-08-01
影响因子：
12.4
通讯作者：
Duplaa, Cecile
中科院分区：
文献类型：
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作者：
Leroux, Lionel;Descamps, Betty;Duplaa, Cecile
间充质干细胞(MSC)是一种多能的出生后干细胞，参与治疗缺血性血管疾病。我们在一个后肢缺血的活体模型中研究了暴露于短期低氧条件下的MSC参与血管和组织再生的能力。移植低氧预适应的小鼠MSC(HypMSC)可促进第7天骨骼肌再生，改善血流和血管形成，与注射的非预适应MSC(NormMSC)相比。这些观察到的效应与HypMSC植入的增加和在坏死性骨骼肌纤维清除中可能起的作用有关。此外，HypMSC移植导致WNT4(无翅相关MMTV整合位点4)的表达显著增加，我们证明了其在MSC增殖和迁移、内皮细胞(EC)迁移以及成肌细胞分化中的功能意义。此外，抑制HypMSC中Wnt4的表达，在小鼠后肢缺血模型中取消了这些细胞在低氧诱导的血管再生特性。我们的数据表明，低氧预适应在MSC的功能能力中起着关键作用，MSC在原位移位以促进缺血组织的恢复，促进血管细胞动员，并通过旁分泌Wnt依赖机制促进骨骼肌纤维的再生。
Mesenchymal stem cells (MSC) are multipotent postnatal stem cells, involved in the treatment of ischemic vascular diseases. We investigate the ability of MSC, exposed to short-term hypoxic conditions, to participate in vascular and tissue regeneration in an in vivo model of hindlimb ischemia. Transplantation of hypoxic preconditioned murine MSC (HypMSC) enhanced skeletal muscle regeneration at day 7, improved blood flow and vascular formation compared to injected nonpreconditioned MSC (NormMSC). These observed effects were correlated with an increase in HypMSC engraftment and a putative role in necrotic skeletal muscle fiber clearance. Moreover, HypMSC transplantation resulted in a large increase in Wnt4 (wingless-related MMTV integration site 4) expression and we demonstrate its functional significance on MSC proliferation and migration, endothelial cell (EC) migration, as well as myoblast differentiation. Furthermore, suppression of Wnt4 expression in HypMSC, abrogated the hypoxia-induced vascular regenerative properties of these cells in the mouse hindlimb ischemia model. Our data suggest that hypoxic preconditioning plays a critical role in the functional capabilities of MSC, shifting MSC location in situ to enhance ischemic tissue recovery, facilitating vascular cell mobilization, and skeletal muscle fiber regeneration via a paracrine Wnt-dependent mechanism.