Mitochondrial aldehyde dehydrogenase-2 deficiency compromises therapeutic effect of ALDH bright cell on peripheral ischemia

Redox Biol. 2017 Oct:13:196-206. doi: 10.1016/j.redox.2017.05.018. Epub 2017 May 29.

Abstract

The autologous ALDH bright (ALDHbr) cell therapy for ischemic injury is clinically safe and effective, while the underlying mechanism remains elusive. Here, we demonstrated that the glycolysis dominant metabolism of ALDHbr cells is permissive to restore blood flow in an ischemic hind limb model compared with bone marrow mononuclear cells (BMNCs). PCR array analysis showed overtly elevated Aldh2 expression of ALDHbr cells following hypoxic challenge. Notably, ALDHbr cells therapy induced blood flow recovery in this model was reduced in case of ALDH2 deficiency. Moreover, significantly reduced glycolysis flux and increased reactive oxygen species (ROS) levels were detected in ALDHbr cell from Aldh2-/- mice. Compromised effect on blood flow recovery was also noticed post transplanting the human ALDHbr cell from ALDH2 deficient patients (GA or AA genotypes) in this ischemic hindlimb mice model. Taken together, our findings illustrate the indispensable role of ALDH2 in maintaining glycolysis dominant metabolism of ALDHbr cell and advocate that patient's Aldh2 genotype is a prerequisite for the efficacy of ALDHbr cell therapy for peripheral ischemia.

Keywords: ALDH(br) cells; ALDH2; Glycolysis; Ischemia injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase, Mitochondrial / deficiency
  • Aldehyde Dehydrogenase, Mitochondrial / genetics*
  • Aldehyde Dehydrogenase, Mitochondrial / metabolism
  • Animals
  • Bone Marrow Transplantation / adverse effects*
  • Bone Marrow Transplantation / methods
  • Cells, Cultured
  • Extremities / blood supply*
  • Genotype
  • Glycolysis
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Reactive Oxygen Species / metabolism
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / therapy*

Substances

  • Reactive Oxygen Species
  • ALDH2 protein, mouse
  • Aldehyde Dehydrogenase, Mitochondrial