Undifferentiated Wharton's Jelly Mesenchymal Stem Cell Transplantation Induces Insulin-Producing Cell Differentiation and Suppression of T-Cell-Mediated Autoimmunity in Nonobese Diabetic Mice

• Published in: Cell transplantation 2015-08, Vol.24 (8), p.1555-1570
• Main Authors: Tsai, Pei-Jiun, Wang, Hwai-Shi, Lin, Gu-Jiun, Chou, Shu-Cheng, Chu, Tzu-Hui, Chuan, Wen-Ting, Lu, Ying-Jui, Weng, Ying-Jui, Su, Cheng-Hsi, Hsieh, Po-Shiuan, Sytwu, Huey-Kang, Lin, Chi-Hung, Chen, Tien-Hua, Shyu, Jia-Fwu
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; Blood Glucose - analysis; C-Peptide - blood; Cell Differentiation; Cells, Cultured; Cytokines - genetics; Cytokines - metabolism; Diabetes Mellitus, Experimental - mortality; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - therapy; Female; Humans; Insulin - blood; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - cytology; Mice; Mice, Inbred NOD; Survival Rate; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Wharton Jelly - cytology
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/096368914X683016

Type 1 diabetes mellitus is caused by T-cell-mediated autoimmune destruction of pancreatic β-cells. Systemic administration of mesenchymal stem cells (MSCs) brings about their incorporation into a variety of tissues with immunosuppressive effects, resulting in regeneration of pancreatic islets. We previously showed that human MSCs isolated from Wharton's jelly (WJ-MSCs) represent a potential cell source to treat diabetes. However, the underlying mechanisms are unclear. The purpose of this study was to discern whether undifferentiated WJ-MSCs can differentiate into pancreatic insulin-producing cells (IPCs) and modify immunological responses in nonobese diabetic (NOD) mice. Undifferentiated WJ-MSCs underwent lentiviral transduction to express green fluorescent protein (GFP) and then were injected into the retro-orbital venous sinus of NOD mice. Seven days after transplantation, fluorescent islet-like cell clusters in the pancreas were apparent. WJ-MSC-GFP-treated NOD mice had significantly lower blood glucose and higher survival rates than saline-treated mice. Systemic and local levels of autoaggressive T-cells, including T helper 1 cells and IL-17-producing T-cells, were reduced, and regulatory T-cell levels were increased. Furthermore, anti-inflammatory cytokine levels were increased, and dendritic cells were decreased. At 23 days, higher human C-peptide and serum insulin levels and improved glucose tolerance were found. Additionally, WJ-MSCs-GFP differentiated into IPCs as shown by colocalization of human C-peptide and GFP in the pancreas. Significantly more intact islets and less severe insulitis were observed. In conclusion, undifferentiated WJ-MSCs can differentiate into IPCs in vivo with immunomodulatory effects and repair the destroyed islets in NOD mice.