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Robertson, Abigail,Mohamed, Tamer M.A.,El Maadawi, Zeinab,Stafford, Nicholas,Bui, Thuy,Lim, Dae-Sik,Cartwright, Elizabeth J.,Oceandy, Delvac Elsevier 2017 Stem cell research Vol.20 No.-
<▼1><P>Adult fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSC) for use in various applications. However, there are challenges in iPSC generation including low reprogramming efficiency, yield, cell survival and viability. Since the Hippo signalling pathway is a key pathway involved in regulating cell proliferation and survival, we here test whether modification of the Hippo pathway will enhance the efficiency of iPSC generation and improve their survival.</P><P>The Hippo pathway was modified by genetic ablation of the mammalian sterile-20 like kinase 1 (Mst1), a major component of the pathway. Using adult skin fibroblasts isolated from Mst1 knockout mice (Mst1<SUP>−/−</SUP>) as a source of iPSC we found that genetic ablation of Mst1 leads to significantly increased reprogramming efficiency by 43.8%. Moreover, Mst1<SUP>−/−</SUP> iPSC displayed increase proliferation by 12% as well as an increase in cell viability by 20% when treated with a chemical hypoxic inducer. Mechanistically, we found higher activity of YAP, the main downstream effector of the Hippo pathway, in iPSC lacking Mst1.</P><P>In conclusion, our data suggests that Mst1 can be targeted to improve the efficiency of adult somatic cell reprogramming as well as to enhance iPSC proliferation and survival.</P></▼1><▼2><P><B>Highlights</B></P><P>•<P>Genetic deletion of Mst1 increases the efficiency of cell reprogramming.</P>•<P>iPSC lacking Mst1 displays higher proliferation rate than WT iPSC.</P>•<P>In response to chemical hypoxia Mst1<SUP>−/−</SUP> iPSC demonstrates higher survival.</P></P></▼2>
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The Mammalian Ste20-like Kinase 2 (Mst2) Modulates Stress-induced Cardiac Hypertrophy
Zi, Min,Maqsood, Arfa,Prehar, Sukhpal,Mohamed, Tamer M. A.,Abou-Leisa, Riham,Robertson, Abigail,Cartwright, Elizabeth J.,Ray, Simon G.,Oh, Sangphil,Lim, Dae-Sik,Neyses, Ludwig,Oceandy, Delvac American Society for Biochemistry and Molecular Bi 2014 The Journal of biological chemistry Vol.289 No.35
<P>The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. <I>Mst2</I><SUP>−/−</SUP> mice showed no alteration in cardiomyocyte proliferation. However, <I>Mst2</I><SUP>−/−</SUP> mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of <I>MST2</I> in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human <I>MST2</I> gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart.</P>
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