title: Injection of vessel-derived stem cells prevents dilated cardiomyopathy and promotes angiogenesis and endogenous cardiac stem cell proliferation in mdx/utrn-/- but not aged mdx mouse models for duchenne muscular dystrophy.
abstract: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. DMD patients lack dystrophin protein and develop skeletal muscle pathology and dilated cardiomyopathy (DCM). Approximately 20% succumb to cardiac involvement. We hypothesized that mesoangioblast stem cells (aorta-derived mesoangioblasts [ADMs]) would restore dystrophin and alleviate or prevent DCM in animal models of DMD. ADMs can be induced to express cardiac markers, including Nkx2.5, cardiac tropomyosin, cardiac troponin I, and α-actinin, and adopt cardiomyocyte morphology. Transplantation of ADMs into the heart of mdx/utrn(-/-) mice prior to development of DCM prevented onset of cardiomyopathy, as measured by echocardiography, and resulted in significantly higher CD31 expression, consistent with new vessel formation. Dystrophin-positive cardiomyocytes and increased proliferation of endogenous Nestin(+) cardiac stem cells were detected in ADM-injected heart. Nestin(+) striated cells were also detected in four of five mdx/utrn(-/-) hearts injected with ADMs. In contrast, when ADMs were injected into the heart of aged mdx mice with advanced fibrosis, no functional improvement was detected by echocardiography. Instead, ADMs exacerbated some features of DCM. No dystrophin protein, increase in CD31 expression, or increase in Nestin(+) cell proliferation was detected following ADM injection in aged mdx heart. Dystrophin was observed following transplantation of ADMs into the hearts of young mdx mice, however, suggesting that pathology in aged mdx heart may alter the fate of donor stem cells. In summary, ADMs delay or prevent development of DCM in dystrophin-deficient heart, but timing of stem cell transplantation may be critical for achieving benefit with cell therapy in DMD cardiac muscle.
authors.affiliation: Department of Animal Sciences, University of Illinois, Urbana, IL, USA.
authors.forename: Ju Lan
authors.initials: JL
authors.lastname: Chun
authors.forename: Robert
authors.initials: R
authors.lastname: O'Brien
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Song
authors.forename: Blake F
authors.initials: BF
authors.lastname: Wondrasch
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Berry
mesh_terms: D000367:Age Factors; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001011:Aorta / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D049411:Utrophin / Q000235:genetics
chemical_list: D000943:Antigens, Differentiation; D016189:Dystrophin; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C483600:Utrn protein, mouse; D049411:Utrophin