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

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.

• Authors: Xiaolei Sun, Hong Zhu, Zhen Dong, Xiangwei Liu, Xin Ma, Shasha Han, Fei Lu, Peng Wang, Sanli Qian, Cong Wang, Cheng Shen, Xiaona Zhao, Yunzeng Zou, Junbo Ge, Aijun Sun
• Journal: Redox biology (Redox Biol) Vol. 13 Pg. 196-206 (10 2017) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 28582728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

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

Topics

• Aldehyde Dehydrogenase, Mitochondrial (deficiency, genetics, metabolism)
• Animals
• Bone Marrow Transplantation (adverse effects, 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, metabolism, therapy)