Metabolic reprogramming by HIF-1 promotes the survival of bone marrow-derived angiogenic cells in ischemic tissue

Sergio Rey, Weibo Luo, Larissa A. Shimoda, Gregg L. Semenza

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

A major obstacle to using bone marrow cell-based therapies for ischemic cardiovascular disease is that transplanted cells must survive in an ischemic microenvironment characterized by low oxygen, glucose, and pH. We demonstrate that treatment of bone marrow-derived angiogenic cells (BMDACs) with dimethyloxalylglycine, an α-ketoglutarate antagonist that induces hypoxia-inducible factor 1 (HIF-1) activity, results in metabolic reprogramming of these cells, with increased glucose uptake, decreased O2 consumption, increased lactate production, decreased reactive oxygen species, and increased intracellular pH. These effects are dependent on HIF-1, which transactivates target genes encoding metabolic enzymes and membrane transporters. Dimethyloxalylglycine-treated BMDACs have a significant survival advantage under conditions of low O2 and low pH ex vivo and in ischemic tissue. Combined HIF-1α-based gene and cell therapy reduced tissue necrosis even when BMDAC donors and ischemic recipient mice were 17 months old, suggesting that this approach may have therapeutic utility in elderly patients with critical limb ischemia.

Original languageEnglish (US)
Pages (from-to)4988-4998
Number of pages11
JournalBlood
Volume117
Issue number18
DOIs
StatePublished - May 5 2011

Fingerprint

Hypoxia-Inducible Factor 1
Bone
Bone Marrow
Tissue
Cell- and Tissue-Based Therapy
Glucose
Gene encoding
Membrane Transport Proteins
Bone Marrow Cells
Genetic Therapy
Lactic Acid
Reactive Oxygen Species
Necrosis
Cardiovascular Diseases
Ischemia
Extremities
Genes
Cells
Tissue Donors
Oxygen

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Metabolic reprogramming by HIF-1 promotes the survival of bone marrow-derived angiogenic cells in ischemic tissue. / Rey, Sergio; Luo, Weibo; Shimoda, Larissa A.; Semenza, Gregg L.

In: Blood, Vol. 117, No. 18, 05.05.2011, p. 4988-4998.

Research output: Contribution to journalArticle

Rey, Sergio ; Luo, Weibo ; Shimoda, Larissa A. ; Semenza, Gregg L. / Metabolic reprogramming by HIF-1 promotes the survival of bone marrow-derived angiogenic cells in ischemic tissue. In: Blood. 2011 ; Vol. 117, No. 18. pp. 4988-4998.
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