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Human Adipose-Derived Mesenchymal Stem Cells Respond to Short-Term Hypoxia by Secreting Factors Beneficial for Human Islets In Vitro and Potentiate Antidiabetic Effect In Vivo
Oslo Univ Hosp, Dept Transplant Med, Oslo, Norway;Oslo Univ Hosp, Inst Surg Res, Oslo, Norway;Univ Oslo, Inst Clin Med, Oslo, Norway.
Oslo Univ Hosp, Sect Cell Therapy, Oslo, Norway;Oslo Univ Hosp, Dept Immunol & Transfus Med, Oslo, Norway.
Oslo Univ Hosp, Inst Canc Res, Oslo, Norway.
Oslo Univ Hosp, Sect Cell Therapy, Oslo, Norway.
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2017 (English)In: Cell Medicine, ISSN 2155-1790, E-ISSN 2155-1790, Vol. 9, no 3, p. 103-116Article in journal (Refereed) Published
Abstract [en]

Adipose-derived mesenchymal stem cells (ASCs) release factors beneficial for islets in vitro and protect against hyperglycemia in rodent models of diabetes. Oxygen tension has been shown to induce metabolic changes and alter ASCs' release of soluble factors. The effects of hypoxia on the antidiabetic properties of ASCs have not been explored. To investigate this, we incubated human ASCs for 48 h in 21% (normoxia) or 1% O-2 (hypoxia) and compared viability, cell growth, surface markers, differentiation capability, and soluble factors in the conditioned media (CM). Human islets were exposed to CM from ASCs incubated in either normoxia or hypoxia, and islet function and apoptosis after culture with or without proinflammatory cytokines were measured. To test hypoxic preconditioned ASCs' islet protective effects in vivo, ASCs were incubated for 48 h in normoxia or hypoxia before being injected into Balb/c Rag 1(-/-) immunodeficient mice with streptozotocin-induced insulitis. Progression of diabetes and insulin content of pancreas were measured. We found that incubation in hypoxia was well tolerated by ASCs and that levels of VEGF-A, FGF-2, and bNGF were elevated in CM from ASCs incubated in hypoxia compared to normoxia. while levels of HGF, IL-8, and CXCL1 were reduced. CM from ASCs incubated in hypoxia significantly improved human islet function and reduced apoptosis after culture, and reduced cytokine-induced apoptosis. In our mouse model, pancreas insulin content was higher in both groups receiving ASCs compared to control, but the mice receiving preconditioned ASCs had lower random and fasting blood glucose, as well as improved oral glucose tolerance compared to untreated mice. In conclusion, our in vitro results indicate that the islet protective potential of ASCs improves in hypoxia, and we give insight into factors involved in this. Finally we show that hypoxic preconditioning potentiates ASCs' anti-diabetic effect in vivo.

Place, publisher, year, edition, pages
2017. Vol. 9, no 3, p. 103-116
Keywords [en]
Adipose-derived stem cells (ASCs), Hypoxia, Islet transplantation, Diabetes
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-359793DOI: 10.3727/215517917X693401ISI: 000439429400004PubMedID: 28713640OAI: oai:DiVA.org:uu-359793DiVA, id: diva2:1250460
Funder
EU, FP7, Seventh Framework Programme, 222741Available from: 2018-09-24 Created: 2018-09-24 Last updated: 2018-09-24Bibliographically approved

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Korsgren, Olle

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