title: Genetic ablation of the mammalian sterile-20 like kinase 1 (Mst1) improves cell reprogramming efficiency and increases induced pluripotent stem cell proliferation and survival.
abstract: 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. 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-/-) as a source of iPSC we found that genetic ablation of Mst1 leads to significantly increased reprogramming efficiency by 43.8%. Moreover, Mst1-/-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. 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.
authors.affiliation: Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Abigail
authors.initials: A
authors.lastname: Robertson
authors.affiliation: Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; J. David Gladstone Research Institutes, San Francisco, CA, USA; Faculty of Pharmacy, Zagazig University, Egypt.
authors.forename: Tamer M A
authors.initials: TM
authors.lastname: Mohamed
authors.affiliation: Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom; Department of Histology and Cell Biology, Faculty of Medicine, Cairo University, Egypt.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: El Maadawi
authors.affiliation: Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stafford
authors.affiliation: Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Thuy
authors.initials: T
authors.lastname: Bui
authors.affiliation: Department of Biological Sciences, KAIST, Daejon, Republic of Korea.
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.affiliation: Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Cartwright
authors.affiliation: Division of Cardiovascular Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom. Electronic address: delvac.oceandy@manchester.ac.uk.
authors.forename: Delvac
authors.initials: D
authors.lastname: Oceandy
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D065150:Cellular Reprogramming; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000172:deficiency / Q000235:genetics*; D000090683:Hippo Signaling Pathway; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases
keywords: Cell proliferation; Hippo pathway; Mst1; Reprogramming; iPSC