Aldehyde Dehydrogenase-2 Is a Host Factor Required for Effective Bone Marrow Mesenchymal Stem Cell Therapy

Abstract

Objective— Mesenchymal stem cell (MSC) therapy is a promising treatment for ischemic injury. However, the environmental regulatory mechanism is essentially unclear and thus greatly limits its application in clinical setting. Accumulating evidence suggests a vital role of aldehyde dehydrogenase-2 (ALDH2) in microenvironment homeostasis after ischemia. About 540 million people or 8% of population worldwide carry a loss-of-function allele of ALDH2. It is unknown whether ALDH2 functions as a host factor regulating the therapeutic potential of donor MSCs. Therefore, this study was designed to determine whether and how host ALDH2 regulates MSC retention and therapeutic efficacy after transplantation into ischemic tissues. Approach and Results— Mice limb ischemia was performed by femoral artery ligation. A total of 10 6 MSCs were injected into the ischemic thigh muscles. One, 2, and 4 weeks after transplantation, MSC retention, blood perfusion recovery, limb necrosis, and fibrosis were analyzed. Compared with wild-type tissue, ALDH2 deficiency tissue significantly limited MSC retention and its perfusion recovery and limb salvage effects after ischemia. Importantly, local overexpression of ALDH2 optimized tissue microenvironment and significantly magnified all these MSC-induced improvement. Further study indicated that host ALDH2 regulated transplanted MSC survival and therapy as a microenvironment homeostasis mediator via local capillary density, energy supply, and oxidative stress regulating after ischemia. Conclusions— Our study establishes ALDH2 as a key mediator of host stem cell niche for optimal MSC therapy and suggests that ALDH2 deficiency present in the general population is a limiting host factor to be considered for MSC therapy.