Human umbilical cord matrix-derived stem cells exert trophic effects on β-cell survival in diabetic rats and isolated islets.
Human umbilical cord matrix-derived stem cells exert trophic effects on β-cell survival in diabetic rats and isolated islets.
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DOI：
10.1242/dmm.021857
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发表时间：
2015-12
影响因子：
4.3
通讯作者：
Ho G
中科院分区：
文献类型：
--
作者：
Zhou Y;Hu Q;Chen F;Zhang J;Guo J;Wang H;Gu J;Ma L;Ho G
人脐带基质干细胞 (uMSC) 与其他组织来源的间充质干细胞相比，由于其细胞和获取优势，目前正处于治疗 1 型 (T1D) 和 2 型糖尿病 (T2D) 的临床试验中。然而，治疗基础仍有待充分了解。 uMSCs 的免疫调节特性可以解释其在治疗 T1D 中的用途；然而，仅仅免疫调节可能不足以支持在 T2D 中的使用。因此，我们测试了uMSCs是否可以对β细胞产生直接的营养作用。将uMSCs输注到化学诱导的糖尿病大鼠中可防止高血糖进展，同时保留胰岛大小和细胞结构，这证明了uMSCs对β细胞的保护作用。机制分析表明，uMSCs 长期植入受损的胰腺中，并且植入显着激活了胰腺 PI3K 通路及其下游抗凋亡机制。促生存途径的激活与uMSCs表达和分泌β细胞生长因子有关，其中胰岛素样生长因子1（IGF1）含量很高。为了确定 uMSC 分泌因子与 β 细胞存活之间的因果关系，将分离的大鼠胰岛与 uMSC 在 Transwell 系统中共培养。共培养改善了胰岛活力和胰岛素分泌。此外，通过 siRNA 敲低减少 uMSC 分泌的 IGF1 降低了对共培养中胰岛的保护作用。因此，我们的数据支持 uMSC 通过分泌 IGF1 等 β 细胞生长因子对胰岛发挥营养作用的模型。该研究揭示了 uMSC 的新治疗作用，并表明 uMSC 采用多种机制来治疗糖尿病。摘要：新发现的脐带干细胞的旁分泌作用凸显了它们不仅可以治疗自身免疫介导的 1 型糖尿病，还可以治疗 2 型糖尿病。
Human umbilical cord matrix-derived stem cells (uMSCs), owing to their cellular and procurement advantages compared with mesenchymal stem cells derived from other tissue sources, are in clinical trials to treat type 1 (T1D) and type 2 diabetes (T2D). However, the therapeutic basis remains to be fully understood. The immunomodulatory property of uMSCs could explain the use in treating T1D; however, the mere immune modulation might not be sufficient to support the use in T2D. We thus tested whether uMSCs could exert direct trophic effects on β-cells. Infusion of uMSCs into chemically induced diabetic rats prevented hyperglycemic progression with a parallel preservation of islet size and cellularity, demonstrating the protective effect of uMSCs on β-cells. Mechanistic analyses revealed that uMSCs engrafted long-term in the injured pancreas and the engraftment markedly activated the pancreatic PI3K pathway and its downstream anti-apoptotic machinery. The pro-survival pathway activation was associated with the expression and secretion of β-cell growth factors by uMSCs, among which insulin-like growth factor 1 (IGF1) was highly abundant. To establish the causal relationship between the uMSC-secreted factors and β-cell survival, isolated rat islets were co-cultured with uMSCs in the transwell system. Co-culturing improved the islet viability and insulin secretion. Furthermore, reduction of uMSC-secreted IGF1 via siRNA knockdown diminished the protective effects on islets in the co-culture. Thus, our data support a model whereby uMSCs exert trophic effects on islets by secreting β-cell growth factors such as IGF1. The study reveals a novel therapeutic role of uMSCs and suggests that multiple mechanisms are employed by uMSCs to treat diabetes. Summary: The newly identified paracrine role of umbilical cord stem cells highlights their therapeutic utilities to treat not only the autoimmune-mediated type 1 diabetes but also type 2 diabetes.