Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis
Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis
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DOI：
10.1172/jci81423
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发表时间：
2015-09-01
影响因子：
15.9
通讯作者：
Stappenbeck, Thaddeus S.
中科院分区：
文献类型：
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作者：
Manieri, Nicholas A.;Mack, Madison R.;Stappenbeck, Thaddeus S.
间充质干细胞(MSC)治疗是再生医学的一个新兴领域；然而，这些细胞如何介导修复通常是不清楚的。在这里，我们研究了间充质干细胞在肠道疾病治疗中的应用，并通过在前列腺素缺乏的小鼠的结肠粘膜上制造局灶性伤口来模拟异常修复。这些伤口发展成溃疡，渗入肠壁外壁。我们确定，在这个模型中，穿透性溃疡的形成是由于缺氧增加和平滑肌壁坏死所致。前列腺素I-2(PGI(2))刺激依赖血管内皮生长因子的血管生成，以防止穿透性溃疡。用VEGFR抑制剂治疗黏膜损伤的WT小鼠，导致穿透性溃疡的发展，进一步证明了血管内皮生长因子对粘膜修复至关重要。接下来，我们使用这个模型来研究移植的结肠间充质干细胞(CMSCs)在肠道修复中的作用。与静脉注射cMSCs相比，黏膜注射cMSCs更有效地防止穿透性溃疡的发展，因为它们更有效地被招募到结肠伤口。重要的是，黏膜注射的cMSCs以一种依赖于血管内皮生长因子的方式刺激血管生成。总之，我们的结果表明，穿透性溃疡的形成是由于减少了局部血管生成，靶向注射MSCs可以优化移植治疗。此外，局部注射MSC具有治疗血管生成和修复异常的疾病的潜力。
Mesenchymal stem cell (MSC) therapy is an emerging field of regenerative medicine; however, it is often unclear how these cells mediate repair. Here, we investigated the use of MSCs in the treatment of intestinal disease and modeled abnormal repair by creating focal wounds in the colonic mucosa of prostaglandin-deficient mice. These wounds developed into ulcers that infiltrated the outer intestinal wall. We determined that penetrating ulcer formation in this model resulted from increased hypoxia and smooth muscle wall necrosis. Prostaglandin I-2 (PGI(2)) stimulated VEGF-dependent angiogenesis to prevent penetrating ulcers. Treatment of mucosally injured WT mice with a VEGFR inhibitor resulted in the development of penetrating ulcers, further demonstrating that VEGF is critical for mucosal repair. We next used this model to address the role of transplanted colonic MSCs (cMSCs) in intestinal repair. Compared with intravenously injected cMSCs, mucosally injected cMSCs more effectively prevented the development of penetrating ulcers, as they were more efficiently recruited to colonic wounds. Importantly, mucosally injected cMSCs stimulated angiogenesis in a VEGF-dependent manner. Together, our results reveal that penetrating ulcer formation results from a reduction of local angiogenesis and targeted injection of MSCs can optimize transplantation therapy. Moreover, local MSC injection has potential for treating diseases with features of abnormal angiogenesis and repair.