title: Injection of wild type embryonic stem cells into Mst1 transgenic blastocysts prevents adult-onset cardiomyopathy.
abstract: Embryonic stem cells have the capacity to differentiate into a wide range of cell types. We previously described that blastocyst injection of wild type (WT) embryonic stem cells (ESCs) into various knockout (KO) mouse models of human disease prevents disease from occurring. In this study we ask if the blastocyst approach can also correct defects in a mouse model of transgenic (Tg) overexpression of a pro-apoptotic factor. We injected ROSA26 (LacZ-marked) WT ESCs into human mammalian sterile 20 like-kinase 1 (Mst1) Tg blastocysts. Mst1 Tg mice overexpress Mst1, a pro-apoptotic factor, in a cardiac-specific manner. As a result, Mst1 Tg mice develop adult dilated cardiomyopathy driven by apoptosis, reduction in cell density and no hypertrophic compensation. Incorporation of WT ESCs generated WT/Mst1 chimeric mice with normal hearts at histological and functional levels. Accordingly, apoptosis and cell density parameters were normalized. The experiments suggest that an adult-onset cardiac myopathy induced by overexpression of the pro-apoptotic Mst1 can be reversed by developmental incorporation of WT ESCs. The findings also suggest that since forced expression of the Mst1 transgene is not abolished in the rescued chimeras, the WT ES-derived cells normalize pathways that lie downstream of Mst1. The results expand the therapeutic capability of the ESCs to mouse models that overproduce detrimental proteins.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ, Newark, NJ, USA.
authors.forename: Qingshi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Beck
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Vitale
authors.forename: Joel S
authors.initials: JS
authors.lastname: Schneider
authors.forename: Corey
authors.initials: C
authors.lastname: Chang
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Dominic
authors.initials: D
authors.lastname: del Re
authors.forename: Mantu
authors.initials: M
authors.lastname: Bhaumik
authors.forename: Ghassan
authors.initials: G
authors.lastname: Yehia
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
authors.forename: Diego
authors.initials: D
authors.lastname: Fraidenraich
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology*; D009202:Cardiomyopathies / Q000378:metabolism / Q000517:prevention & control*; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099317:Hippo Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C095566:STK4 protein, human; D000099317:Hippo Kinases