title: Role of WNT/β-catenin signaling in rejuvenating myogenic differentiation of aged mesenchymal stem cells from cardiac patients.
abstract: Autologous stem cell therapy has not been as effective as forecasted from preclinical studies. Patient age was reported as an important contributing factor. The goal of this study was to uncover age-dependent mechanisms of stem cell dysfunction and to investigate possible means to restore the cellular function. Bone marrow mesenchymal stem cells (MSCs) were isolated from cardiovascular patients. Cell proliferation and number of colonies were inversely correlated with patient age. Myogenic differentiation of MSCs in culture was induced with 5-azacytidine. Differentiation correlated with age, with less differentiation in MSCs from aged patients. We performed real-time PCR to identify genes in the WNT/β-catenin signaling network and found that transcript levels of CTNNB1, LEF1, FZD8, WNT3A, and SFRP4 were negatively correlated with age, whereas FOSL1, LRP6, and FZD6 were positively correlated with age. Protein evaluation showed that β-catenin nuclear translocation correlated with age and was lower in aged MSCs. Aged MSCs treated with lithium chloride-to increase the bioavailability of β-catenin-recovered their capacity for myogenic differentiation through myocyte enhancer factor 2C but not with the knockdown of β-catenin using small-interfering RNA. This study may be the first to relate reduced nuclear β-catenin bioavailability in MSCs from aged patients. Most important, this abnormality was potentially recoverable, providing a target for improving the function of bone marrow stem cells and their clinical utility in aged patients.
authors.affiliation: Division of Cardiovascular Surgery and Toronto General Research Institute, University Health Network, University of Toronto, Ontario, Canada.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Brunt
authors.forename: Yuemei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anton
authors.initials: A
authors.lastname: Mihic
authors.forename: Mingxi
authors.initials: M
authors.lastname: Li
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Phil
authors.initials: P
authors.lastname: Xue
authors.forename: William
authors.initials: W
authors.lastname: Zhang
authors.forename: Samir
authors.initials: S
authors.lastname: Basmaji
authors.forename: Katherine
authors.initials: K
authors.lastname: Tsang
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Yau
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000473:pathology*; D002318:Cardiovascular Diseases / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D024510:Muscle Development / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D014019:Tissue Donors; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin; D008094:Lithium