title: Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: analysis of hASC-derived paracrine effectors.
abstract: Adipose-derived stromal/stem cells (ASCs) ameliorate hyperglycemia in rodent models of islet transplantation and autoimmune diabetes, yet the precise human ASC (hASC)-derived factors responsible for these effects remain largely unexplored. Here, we show that systemic administration of hASCs improved glucose tolerance, preserved β cell mass, and increased β cell proliferation in streptozotocin-treated nonobese diabetic/severe combined immunodeficient mice. Coculture experiments combining mouse or human islets with hASCs demonstrated that islet viability and function were improved by hASCs following prolonged culture or treatment with proinflammatory cytokines. Analysis of hASC-derived factors revealed vascular endothelial growth factor and tissue inhibitor of metalloproteinase 1 (TIMP-1) to be highly abundant factors secreted by hASCs. Notably, TIMP-1 secretion increased in the presence of islet stress from cytokine treatment, while TIMP-1 blockade was able to abrogate in vitro prosurvival effects of hASCs. Following systemic administration by tail vein injection, hASCs were detected in the pancreas and human TIMP-1 was increased in the serum of injected mice, while recombinant TIMP-1 increased viability in INS-1 cells treated with interleukin-1beta, interferon-gamma, and tumor necrosis factor alpha. In aggregate, our data support a model whereby factors secreted by hASCs, such as TIMP-1, are able to mitigate against β cell death in rodent and in vitro models of type 1 diabetes through a combination of local paracrine as well as systemic effects.
authors: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors: Tatsuyoshi M
authors: TM
authors: Kono
authors: Emily K
authors: EK
authors: Sims
authors: Dan R
authors: DR
authors: Moss
authors: Wataru
authors: W
authors: Yamamoto
authors: Geonyoung
authors: G
authors: Ahn
authors: Julie
authors: J
authors: Diamond
authors: Xin
authors: X
authors: Tong
authors: Kathleen H
authors: KH
authors: Day
authors: Paul R
authors: PR
authors: Territo
authors: Helmut
authors: H
authors: Hanenberg
authors: Dmitry O
authors: DO
authors: Traktuev
authors: Keith L
authors: KL
authors: March
authors: Carmella
authors: C
authors: Evans-Molina
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism / Q000637:transplantation*; D000818:Animals; D048429:Cell Size; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000628:therapy*; D005260:Female; D018149:Glucose Intolerance; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000628:therapy*; D050417:Insulin-Secreting Cells / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019899:Paracrine Communication; D013311:Streptozocin; D050151:Subcutaneous Fat / Q000166:cytology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D013311:Streptozocin
keywords: Adipose stem cells; Caspase; Cellular proliferation; Diabetes; Pancreas; Tissue regeneration