School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
Int J Mol Sci. 2019 Aug 21;20(17):4083. doi: 10.3390/ijms20174083.
Pancreatic progenitor cells (PPCs) are the primary source for all pancreatic cells, including beta-cells, and thus the proliferation and differentiation of PPCs into islet-like cell clusters (ICCs) opens an avenue to providing transplantable islets for diabetic patients. Meanwhile, mesenchymal stem cells (MSCs) can enhance the development and function of different cell types of interest, but their role on PPCs remains unknown. We aimed to explore the mechanism-of-action whereby MSCs induce the in vitro and in vivo PPC/ICC development by means of our established co-culture system of human PPCs with human fetal bone marrow-derived MSCs. We examined the effect of MSC-conditioned medium on PPC proliferation and survival. Meanwhile, we studied the effect of MSC co-culture enhanced PPC/ICC function in vitro and in vivo co-/transplantation. Furthermore, we identified IGF1 as a critical factor responsible for the MSC effects on PPC differentiation and proliferation via IGF1-PI3K/Akt and IGF1-MEK/ERK1/2, respectively. In conclusion, our data indicate that MSCs stimulated the differentiation and proliferation of human PPCs via IGF1 signaling, and more importantly, promoted the in vivo engraftment function of ICCs. Taken together, our protocol may provide a mechanism-driven basis for the proliferation and differentiation of PPCs into clinically transplantable islets.
胰腺祖细胞 (PPCs) 是所有胰腺细胞（包括β细胞）的主要来源，因此 PPCs 增殖和分化为胰岛样细胞簇 (ICCs) 为糖尿病患者提供了可移植的胰岛细胞。同时，间充质干细胞 (MSCs) 可以增强不同感兴趣的细胞类型的发育和功能，但它们在 PPCs 上的作用尚不清楚。我们旨在通过我们建立的人 PPCs 与人胎儿骨髓来源的 MSCs 的共培养系统，探索 MSCs 诱导 PPC/ICC 体外和体内发育的作用机制。我们检查了 MSC 条件培养基对 PPC 增殖和存活的影响。同时，我们研究了 MSC 共培养增强 PPC/ICC 功能的体外和体内共/移植的效果。此外，我们通过 IGF1-PI3K/Akt 和 IGF1-MEK/ERK1/2 分别确定 IGF1 是 MSC 对 PPC 分化和增殖作用的关键因素。总之，我们的数据表明，MSCs 通过 IGF1 信号刺激人 PPCs 的分化和增殖，更重要的是，促进了 ICCs 的体内植入功能。综上所述，我们的方案可能为 PPCs 增殖和分化为临床可移植的胰岛细胞提供了一种基于机制的基础。
