Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK.
Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK.
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DOI：
10.1186/1423-0127-17-56
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发表时间：
2010-07-12
影响因子：
11
通讯作者：
Hung SC
中科院分区：
文献类型：
--
作者：
Lin HY;Tsai CC;Chen LL;Chiou SH;Wang YJ;Hung SC
胰岛移植为治疗1型糖尿病提供了一个有希望的方法；然而，它受到胰腺捐赠者短缺的限制。骨髓来源的多能间充质干细胞（MSCs）为生成胰岛素生成细胞（IPCs）提供了可再生的细胞。我们采用四阶段分化方案，包括神经元分化和IPC转化阶段，并结合颗粒悬浮培养诱导IPC分化。在这里，我们报告了添加细胞外基质蛋白（ECM），如纤维连接蛋白（FN）或层粘连蛋白（LAM），通过增加胰岛素和Glut2基因表达、胰岛素原和胰岛素蛋白水平以及胰岛素释放来增强胰腺分化，以响应葡萄糖浓度升高。添加FN或LAM诱导Akt和ERK活化。通过添加LY294002 （PI3K特异性抑制剂）、PD98059 （MEK特异性抑制剂）或抑制Akt或ERK来阻断Akt或ERK不能消除FN或lam诱导的IPC分化增强。仅阻断Akt和ERK或敲低Akt和ERK可通过添加ECM增强IPC分化。这些数据证明MSCs的IPC分化可以通过添加ECM来调节，这些刺激作用是通过激活Akt和ERK途径介导的。
Islet transplantation provides a promising cure for Type 1 diabetes; however it is limited by a shortage of pancreas donors. Bone marrow-derived multipotent mesenchymal stem cells (MSCs) offer renewable cells for generating insulin-producing cells (IPCs). We used a four-stage differentiation protocol, containing neuronal differentiation and IPC-conversion stages, and combined with pellet suspension culture to induce IPC differentiation. Here, we report adding extracellular matrix proteins (ECM) such as fibronectin (FN) or laminin (LAM) enhances pancreatic differentiation with increases in insulin and Glut2 gene expressions, proinsulin and insulin protein levels, and insulin release in response to elevated glucose concentration. Adding FN or LAM induced activation of Akt and ERK. Blocking Akt or ERK by adding LY294002 (PI3K specific inhibitor), PD98059 (MEK specific inhibitor) or knocking down Akt or ERK failed to abrogate FN or LAM-induced enhancement of IPC differentiation. Only blocking both of Akt and ERK or knocking down Akt and ERK inhibited the enhancement of IPC differentiation by adding ECM. These data prove IPC differentiation by MSCs can be modulated by adding ECM, and these stimulatory effects were mediated through activation of Akt and ERK pathways.