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.

Alda-1 treatment promotes the therapeutic effect of mitochondrial transplantation for myocardial ischemia-reperfusion injury

“…ALDH2 activity regulates mitochondrial homeostasis and function by combating oxidative stress [ 20 , 33 ]. Therefore, we treated mitochondria with ALDH2 activator, Alda-1, to determine the effect on mitochondrial respiration.…”

“…As a mitochondrial enzyme, ALDH2 plays a pivotal role in sustaining the mitochondrial homeostasis of cardiomyocytes [ 19 , 20 , 45 ]. Our previous studies elucidated that ALDH2 deficiency [ 20 , 33 ] or inhibition [ 46 ] stimulated ROS over-production in mitochondria, ultimately resulting in exacerbated cardiomyocyte apoptosis in response to hypoxia. Thus, the close relationship between ALDH2 activity and mitochondrial homeostasis prompted the present study on ALDH2 activation in mitochondrial transplantation.…”

“…The oxygen consumption rates (OCRs) of cardiomyocytes in different treatment groups were analyzed using an XFe96 extracellular flux analyzer (Seahorse Bioscience, Billerica, MA, USA) as described previously [ 33 ]. The metabolic OCR profiles were detected by adding oligomycin A (1 μM), 1 μM FCCP, antimycin A (1 μM), and rotenone (1 μM).…”

Foreskin-derived mesenchymal stromal cells with aldehyde dehydrogenase activity: isolation and gene profiling

“…A recent study reported that low expression of ALDH in decidual MSC (DMSC) isolated from preeclamptic (PE) patients is associated with reduced resistance to cell toxicity. In line, stem and progenitor cells expressing high level of ALDH were shown to be clinically safe and effective cell therapy for peripheral ischemia [ 42 ]. These cyto-protective enzymes may thus potentiate cell therapy by serving as markers of highly therapeutic MSCs that harbor specific competencies.…”

Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia

“…High level of oxidative phosphorylation in mitochondria has been known to produce oxidative stress such as ROS. On the other hand, previous studies provided evidences that ALDH family proteins help alleviate intracellular ROS (36)(37)(38). The underlying mechanism is attributable to their capability in clearage of cellular aldehydes, which are known as ROS inducer (39)(40)(41).…”