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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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
Publication statusPublished - Aug 19 2015

Fingerprint

Wharton Jelly
Mesenchymal Stem Cell Transplantation
Inbred NOD Mouse
T-cells
Insulin
Stem cells
Autoimmunity
Mesenchymal Stromal Cells
Cell Differentiation
T-Lymphocytes
Green Fluorescent Proteins
C-Peptide
Medical problems
Proteins
Islets of Langerhans
Peptides
Glucose
Pancreas
Th1 Cells
Interleukin-17

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation
  • Biomedical Engineering
  • Medicine(all)

Cite this

Undifferentiated Wharton’s jelly mesenchymal stem cell transplantation induces insulin-producing cell differentiation and suppression of T-cell-mediated autoimmunity in nonobese diabetic mice. / Tsai, Pei Jiun; Wang, Hwai Shi; Lin, Gu Jiun; Chou, Shu Cheng; Chu, Tzu Hui; Chuan, Wen Ting; Lu, Ying Jui; Weng, Zen Chung; Su, Cheng Hsi; Hsieh, Po Shiuan; Sytwu, Huey Kang; Lin, Chi Hung; Chen, Tien Hua; Shyu, Jia Fwu.

In: Cell Transplantation, Vol. 24, No. 8, 19.08.2015, p. 1555-1570.

Research output: Contribution to journalArticle

Tsai, PJ, Wang, HS, Lin, GJ, Chou, SC, Chu, TH, Chuan, WT, Lu, YJ, Weng, ZC, Su, CH, Hsieh, PS, Sytwu, HK, Lin, CH, Chen, TH & Shyu, JF 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, vol. 24, no. 8, pp. 1555-1570. https://doi.org/10.3727/096368914X683016
Tsai, Pei Jiun ; Wang, Hwai Shi ; Lin, Gu Jiun ; Chou, Shu Cheng ; Chu, Tzu Hui ; Chuan, Wen Ting ; Lu, Ying Jui ; Weng, Zen Chung ; Su, Cheng Hsi ; Hsieh, Po Shiuan ; Sytwu, Huey Kang ; Lin, Chi Hung ; Chen, Tien Hua ; Shyu, Jia Fwu. / Undifferentiated Wharton’s jelly mesenchymal stem cell transplantation induces insulin-producing cell differentiation and suppression of T-cell-mediated autoimmunity in nonobese diabetic mice. In: Cell Transplantation. 2015 ; Vol. 24, No. 8. pp. 1555-1570.
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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.",
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