Journal
CELL TRANSPLANTATION
Volume 24, Issue 8, Pages 1555-1570Publisher
SAGE PUBLICATIONS INC
DOI: 10.3727/096368914X683016
Keywords
Wharton's jelly; Mesenchymal stem cells (MSCs); Insulin-producing cells (IPCs); Immunomodulation; NOD mice
Funding
- Taipei VGH [V103D-001-1]
- National Science Council [NSC-102-2314-B-010-041-MY3]
- National Defense Medical Center [MAB-102-56]
- Tri-Service General Hospital [TSGH-C102-124]
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Type 1 diabetes mellitus is caused by T-cell-mediated autoimmune destruction of pancreatic beta-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.
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