title: Human umbilical cord matrix-derived stem cells exert trophic effects on β-cell survival in diabetic rats and isolated islets.
abstract: Human umbilical cord matrix-derived stem cells (uMSCs), owing to their cellular and procurement advantages compared with mesenchymal stem cells derived from other tissue sources, are in clinical trials to treat type 1 (T1D) and type 2 diabetes (T2D). However, the therapeutic basis remains to be fully understood. The immunomodulatory property of uMSCs could explain the use in treating T1D; however, the mere immune modulation might not be sufficient to support the use in T2D. We thus tested whether uMSCs could exert direct trophic effects on β-cells. Infusion of uMSCs into chemically induced diabetic rats prevented hyperglycemic progression with a parallel preservation of islet size and cellularity, demonstrating the protective effect of uMSCs on β-cells. Mechanistic analyses revealed that uMSCs engrafted long-term in the injured pancreas and the engraftment markedly activated the pancreatic PI3K pathway and its downstream anti-apoptotic machinery. The pro-survival pathway activation was associated with the expression and secretion of β-cell growth factors by uMSCs, among which insulin-like growth factor 1 (IGF1) was highly abundant. To establish the causal relationship between the uMSC-secreted factors and β-cell survival, isolated rat islets were co-cultured with uMSCs in the transwell system. Co-culturing improved the islet viability and insulin secretion. Furthermore, reduction of uMSC-secreted IGF1 via siRNA knockdown diminished the protective effects on islets in the co-culture. Thus, our data support a model whereby uMSCs exert trophic effects on islets by secreting β-cell growth factors such as IGF1. The study reveals a novel therapeutic role of uMSCs and suggests that multiple mechanisms are employed by uMSCs to treat diabetes.
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Yunting
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Fuyi
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular Pathology, Shantou University Medical College, Shantou 515041, China.
authors.forename: Jincheng
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular Pathology, Shantou University Medical College, Shantou 515041, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Pediatrics, The Women and Children's Hospital of Shenzhen University, Shenzhen 518122, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China guyuh@yahoo.com.
authors.forename: Guyu
authors.initials: G
authors.lastname: Ho
mesh_terms: D000818:Animals; D002470:Cell Survival; D018920:Coculture Techniques; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology* / Q000628:therapy*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology / Q000628:therapy; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D013311:Streptozocin; D014022:Tissue Survival; D014470:Umbilical Cord / Q000166:cytology*; D015431:Weight Loss
chemical_list: D013311:Streptozocin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases
keywords: Diabetes; Growth factors; IGF1; Stem cells; β-cells