Undifferentiated Wharton’s jelly mesenchymal stem cell transplantation induces insulin-producing cell differentiation and suppression of T-cell-mediated autoimmunity in nonobese diabetic mice

Pei Jiun Tsai, Hwai Shi Wang, Gu Jiun Lin, Shu Cheng Chou, Tzu Hui Chu, Wen Ting Chuan, Ying Jui Lu, Zen Chung Weng, Cheng Hsi Su, Po Shiuan Hsieh, Huey Kang Sytwu, Chi Hung Lin, Tien Hua Chen, Jia Fwu Shyu*

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Type 1 diabetes mellitus is caused by T-cell-mediated autoimmune destruction of pancreatic b-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-GFPtreated 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.

Original languageEnglish
Pages (from-to)1555-1570
Number of pages16
JournalCell Transplantation
Volume24
Issue number8
DOIs
StatePublished - 19 Aug 2015

Keywords

  • Immunomodulation
  • Insulin-producing cells (IPCs)
  • Mesenchymal stem cells (MSCs)
  • NOD mice
  • Wharton’s jelly

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    Tsai, P. J., Wang, H. S., Lin, G. J., Chou, S. C., Chu, T. H., Chuan, W. T., Lu, Y. J., Weng, Z. C., Su, C. H., Hsieh, P. S., Sytwu, H. K., Lin, C. H., Chen, T. H., & Shyu, J. F. (2015). Undifferentiated Wharton’s jelly mesenchymal stem cell transplantation induces insulin-producing cell differentiation and suppression of T-cell-mediated autoimmunity in nonobese diabetic mice. Cell Transplantation, 24(8), 1555-1570. https://doi.org/10.3727/096368914X683016