title: 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.
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.
authors.forename: Pei-Jiun
authors.initials: PJ
authors.lastname: Tsai
authors.forename: Hwai-Shi
authors.initials: HS
authors.lastname: Wang
authors.forename: Gu-Jiun
authors.initials: GJ
authors.lastname: Lin
authors.forename: Shu-Cheng
authors.initials: SC
authors.lastname: Chou
authors.forename: Tzu-Hui
authors.initials: TH
authors.lastname: Chu
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Chuan
authors.forename: Ying-Jui
authors.initials: YJ
authors.lastname: Lu
authors.forename: Zen-Chung
authors.initials: ZC
authors.lastname: Weng
authors.forename: Cheng-Hsi
authors.initials: CH
authors.lastname: Su
authors.forename: Po-Shiuan
authors.initials: PS
authors.lastname: Hsieh
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.forename: Tien-Hua
authors.initials: TH
authors.lastname: Chen
authors.forename: Jia-Fwu
authors.initials: JF
authors.lastname: Shyu
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D016688:Mice, Inbred NOD; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D059631:Wharton Jelly / Q000166:cytology*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D016207:Cytokines; D007328:Insulin