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

Abstract

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.

The Use of Human Mesenchymal Stem Cells as Therapeutic Agents for the in vivo Treatment of Immune-Related Diseases: A Systematic Review

“…A total of 69 out of the 132 articles selected isolated hMSCs from the bone marrow ( 35 , 37 , 42 – 45 , 47 , 49 – 58 , 60 , 62 – 64 , 66 – 73 , 77 , 79 , 80 , 92 , 95 , 98 , 99 , 102 , 107 , 108 , 110 , 111 , 115 – 118 , 122 , 123 , 125 – 128 , 131 , 132 , 133 , 134 , 135 , 137 , 138 , 143 , 146 , 148 – 150 , 154 – 158 , 161 ). In addition, other common sources of hMSCs included the umbilical cord blood or stroma [29 articles ( 36 , 38 , 39 , 41 , 46 , 61 , 65 , 75 , 76 , 78 , 82 , 85 , 89 , 91 , 93 , 95 , 97 , 100 , 101 , 103 , 107 , 113 , 119 , 124 , …”

Mesenchymal stem cell therapy in type 2 diabetes mellitus

“…Chao et al successfully differentiated WJ-MSCs into IPCs through a stepwise culture protocol using neuron-conditioned medium in vitro and proved that the differentiated IPCs exhibit typical beta cell functions in vivo [43]. Tsai et al injected undifferentiated WJ-MSCs expressing green fluorescent protein (GFP) into non-obese diabetic (NOD) mice and observed co-localization of human C-peptide and GFP in the pancreas, indicating that WJ-MSCs differentiated into IPCs in vivo [44]. Wu et al compared the differentiation potential of WJ-MSCs and BM-MSCs.…”

Stem Cells and Regenerative Medicine: Myth or Reality of the 21th Century

“…The first attempt of cell therapy by grafting of islets of Langerhans was published more than ten years ago [ 164 – 167 ]. Other cell sources have also been proposed for pancreas and diabetes cell therapy like adult [ 168 , 169 ] or fetal [ 170 – 172 ] MSC, embryonic stem cells [ 173 – 175 ], or even IPS [ 176 , 177 ] because of their differentiation potential into insulin-producing cells and their immunomodulatory properties. Two studies with different therapeutic approaches are currently investigating the influence of cord blood stem cells on improving the function of pancreatic beta cells.…”