Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia: Analysis of hASC-derived paracrine effectors

Tatsuyoshi Kono, Emily K. Sims, Dan R. Moss, Wataru Yamamoto, Geonyoung Ahn, Julie Diamond, Xin Tong, Kathleen H. Day, Paul Territo, Helmut Hanenberg, Dmitry Traktuev, Keith L. March, Carmella Evans-Molina

Research output: Contribution to journalArticle

34 Citations (Scopus)

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. Stem Cells 2014;32:1831-1842

Original languageEnglish
Pages (from-to)1831-1842
Number of pages12
JournalStem Cells
Volume32
Issue number7
DOIs
StatePublished - 2014

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Tissue Inhibitor of Metalloproteinase-1
Stromal Cells
Hyperglycemia
Stem Cells
Type 1 Diabetes Mellitus
Rodentia
Cytokines
Islets of Langerhans Transplantation
Stem Cell Factor
SCID Mice
Streptozocin
Coculture Techniques
Interleukin-1beta
Vascular Endothelial Growth Factor A
Interferon-gamma
Tail
Pancreas
Veins
Cell Death
Tumor Necrosis Factor-alpha

Keywords

  • Adipose stem cells
  • Caspase
  • Cellular proliferation
  • Diabetes
  • Pancreas
  • Tissue regeneration

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia : Analysis of hASC-derived paracrine effectors. / Kono, Tatsuyoshi; Sims, Emily K.; Moss, Dan R.; Yamamoto, Wataru; Ahn, Geonyoung; Diamond, Julie; Tong, Xin; Day, Kathleen H.; Territo, Paul; Hanenberg, Helmut; Traktuev, Dmitry; March, Keith L.; Evans-Molina, Carmella.

In: Stem Cells, Vol. 32, No. 7, 2014, p. 1831-1842.

Research output: Contribution to journalArticle

Kono, Tatsuyoshi ; Sims, Emily K. ; Moss, Dan R. ; Yamamoto, Wataru ; Ahn, Geonyoung ; Diamond, Julie ; Tong, Xin ; Day, Kathleen H. ; Territo, Paul ; Hanenberg, Helmut ; Traktuev, Dmitry ; March, Keith L. ; Evans-Molina, Carmella. / Human adipose-derived stromal/stem cells protect against STZ-induced hyperglycemia : Analysis of hASC-derived paracrine effectors. In: Stem Cells. 2014 ; Vol. 32, No. 7. pp. 1831-1842.
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AU - Yamamoto, Wataru

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AU - Diamond, Julie

AU - Tong, Xin

AU - Day, Kathleen H.

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AU - Evans-Molina, Carmella

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