title: 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.
  
  
  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.
authors.affiliation: From the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (Hongming Zhu, A.S., Hong Zhu, Z.H., S.Z., X.M., Y.Z., K.H., J.G.), Biomedical Research Center (Z.L.), Zhongshan Hospital, and Institute of Biomedical Science (H.Z.), Fudan University, Shanghai, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Zhu
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Zheyong
authors.initials: Z
authors.lastname: Huang
authors.forename: Shuning
authors.initials: S
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004734:Energy Metabolism; D006614:Hindlimb; D007511:Ischemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000601:surgery*; D023821:Limb Salvage; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D020127:Recovery of Function; D012039:Regional Blood Flow; D055153:Stem Cell Niche; D013997:Time Factors; D014162:Transfection
chemical_list: C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: ALDH2 protein, mouse; angiogenesis; mesenchymal stromal cells; oxidative stress; stem cells