Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo

Julie Beegle, Kinga Lakatos, Stefanos Kalomoiris, Heather Stewart, Roslyn Rivkah Isseroff, Jan Nolta, Fernando A Fierro

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Mesenchymal stem cells/multipotent stromal cells (MSCs) are promising therapeutics for a variety of conditions. However, after transplantation, cell retention remains extremely challenging. Given that many hypoxic signals are transitory and that the therapeutic administration of MSCs is typically into tissues that are normally hypoxic, we studied the effect of hypoxic preconditioning (HP) prior to new exposure to hypoxia. We show that preincubation for 2 days or more in 1% oxygen reduces serum deprivation-mediated cell death, as observed by higher cell numbers and lower incorporation of EthD-III and Annexin V. Consistently, HP-MSCs expressed significantly lower levels of cytochrome c and heme oxygenase 1 as compared to controls. Most importantly, HP-MSCs showed enhanced survival in vivo after intramuscular injection into immune deficient NOD/SCID-IL2Rgamma<sup>-/-</sup> mice. Interestingly, HP-MSCs consume glucose and secrete lactate at a slower rate than controls, possibly promoting cell survival, as glucose remains available to the cells for longer periods of time. In addition, we compared the metabolome of HP-MSCs to controls, before and after hypoxia and serum deprivation, and identified several possible mediators for HP-mediated cell survival. Overall, our findings suggest that preincubation of MSCs for 2 days or more in hypoxia induces metabolic changes that yield higher retention after transplantation.

Original languageEnglish (US)
Pages (from-to)1818-1828
Number of pages11
JournalStem Cells
Volume33
Issue number6
DOIs
StatePublished - Jun 1 2015

Fingerprint

Stromal Cells
Mesenchymal Stromal Cells
Cell Survival
Glucose
Heme Oxygenase-1
SCID Mice
Metabolome
Annexin A5
Intramuscular Injections
Cell Transplantation
Cytochromes c
Serum
Lactic Acid
Cell Death
Cell Count
Transplantation
Oxygen
Therapeutics
Hypoxia

Keywords

  • Hypoxia
  • Mesenchymal stromal cells
  • Metabolism
  • Survival

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo. / Beegle, Julie; Lakatos, Kinga; Kalomoiris, Stefanos; Stewart, Heather; Isseroff, Roslyn Rivkah; Nolta, Jan; Fierro, Fernando A.

In: Stem Cells, Vol. 33, No. 6, 01.06.2015, p. 1818-1828.

Research output: Contribution to journalArticle

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