Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant

Stem Cell Reports. 2017 Sep 12;9(3):807-819. doi: 10.1016/j.stemcr.2017.07.012. Epub 2017 Aug 10.

Abstract

The advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant.

Keywords: graft survival; hypoxia; ischemia; islet transplant; nutrient deprivation; stem cell-derived insulin-producing cells; type 1 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / pharmacology
  • Animals
  • Cell Death / drug effects
  • Cell Hypoxia / drug effects
  • Cytoprotection / drug effects
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Ischemia / pathology
  • Ischemia / therapy*
  • Islets of Langerhans Transplantation*
  • Mice, Inbred C57BL
  • Oxygen / pharmacology
  • Pyruvic Acid / pharmacology
  • Stem Cell Transplantation*
  • Stem Cells / drug effects
  • Stem Cells / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Tissue Survival / drug effects

Substances

  • Amino Acids
  • Pyruvic Acid
  • TOR Serine-Threonine Kinases
  • Oxygen