Mesenchymal Stem Cell-Mediated Survival of Pancreatic Beta Cells Via the Induction of Cellular Signaling Pathways: Akt and Wnt4-Beta-Catenin
Kirby James Taylor
Introduction. Type 1 diabetes mellitus (T1D) is a heterogeneous disorder effecting 1 and 300 Americans characterized by the destruction of pancreatic beta cells, resulting in an insulin deficiency . Beta cells with immune infiltration from CD4+ T cells express specific HLA class II proteins, that cause T-cell mediated destruction . Current treatments for T1D such as exogenous insulin, still come with multiple complications and limitations such as frequent hypoglycemic episodes. Therefore, a major focus of research is to identify methods of improving the number and function of beta cells to postpone the progression of islet destruction in its beginning stages. One particular methodology is the use of mesenchymal stem cells (MSCs) to enhance islet survival by the secretion of a broad range of trophic factors which induce certain cellular signaling pathways to protect islet endothelium and prevent intrinsic apoptosis [3-5]. Two particular cellular signaling pathways are under investigation for islet survival –phosphorylated Akt (p-Akt) and Wnt proteins. Methods. One study investigated the direct humoral interactions between MSC and pancreatic beta-cells using human telomerase-immortalized MSC (hMSC- TERT) and rat beta-cells. hMSC-TERT supported b-cell survival during cellular stress by alloxan (ALX) and streptozotocin (STZ), two compounds inhibiting GLUT2 transport . Another study investigating Wnt signaling used a murine islet microvascular endothelium cell line and an MSC-MS1 transwell culturing system to investigate the protective mechanism of rat bone marrow-derived MSCs under oxidative stress. Cell apoptosis was detected by TUNEL staining, annexin V/PI flow cytometry analysis, and cleaved caspase-3 western blotting analysis. Endothelial cell activation was determined by expression of intercellular cell adhesion molecule and vascular cell adhesion molecule, as well as eNOS phosphorylation/ activation . Results. Through Wnt signaling, MSCs could alleviate endothelial apoptosis and improve its function by promoting eNOS phosphorylation and reducing the expression of adhesion molecules such as VCAM1. MSCs also preserved p-Akt in b-cells and reduced caspase 3/7 activation therefore inhibiting intrinsic apoptosis [4,5]. Conclusion. MSC-induced preservation of Akt signaling reduces b-cell apoptosis when put under cellular stressors; MSC mediated Wnt4-beta-catenin signaling protects the microvasculature of the islet endothelium via inhibiting apoptosis by phosphorylating eNOS and downregulating the transcription of inflammatory adhesion molecules like VCAM [4,5]. These are but a few mechanisms that look promising via the use of MSCs for enhancing Beta cell function and survival.
- Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Epidemiology of type 1 diabetes. Endocrinol Metab Clin North Am. 2010. September;39(3):481–97. 10.1016/j.ecl.2010.05.011 .
- Zhao Y, Scott NA, Quah HS, et al. Mouse pancreatic beta cells express MHC class II and stimulate CD4 T cells to proliferate. European Journal of Immunology. 2015;45(9):2494-2503. doi:10.1002/eji.201445378.
- Päth G, Perakakis N, Mantzoros CS, Seufert J. Stem cells in the treatment of diabetes mellitus — Focus on mesenchymal stem cells. Metabolism. 2019;90:1-15. doi:10.1016/j.metabol.2018.10.005.
- Liu C, Zhang W, Peradze N, et al. Mesenchymal stem cell (MSC)-mediated survival of insulin producing pancreatic β-cells during cellular stress involves signalling via Akt and ERK1/2. Molecular and Cellular Endocrinology. 2018;473:235-244. doi:10.1016/j.mce.2018.01.024.
- Wang, L., Qing, L., Liu, H., Liu, N., Qiao, J., Cui, C., . . . Chen, L. (2017). Mesenchymal stromal cells ameliorate oxidative stress-induced islet endothelium apoptosis and functional impairment via Wnt4-β-catenin signaling. Stem Cell Research & Therapy,8(1). doi:10.1186/s13287-017-0640-0