title: Recent advances in animal and human pluripotent stem cell modeling of cardiac laminopathy.
abstract: Laminopathy is a disease closely related to deficiency of the nuclear matrix protein lamin A/C or failure in prelamin A processing, and leads to accumulation of the misfold protein causing progeria. The resultant disrupted lamin function is highly associated with abnormal nuclear architecture, cell senescence, apoptosis, and unstable genome integrity. To date, the effects of loss in nuclear integrity on the susceptible organ, striated muscle, have been commonly associated with muscular dystrophy, dilated cardiac myopathy (DCM), and conduction defeats, but have not been studied intensively. In this review, we aim to summarize recent breakthroughs in an in vivo laminopathy model and in vitro study using patient-specific human induced pluripotent stem cells (iPSCs) that reproduce the pathophysiological phenotype for further drug screening. We describe several in-vivo transgenic mouse models to elucidate the effects of Lmna H222P, N195K mutations, and LMNA knockout on cardiac function, in terms of hemodynamic and electrical signal propagation; certain strategies targeted on stress-related MAPK are mentioned. We will also discuss human iPSC cardiomyocytes serving as a platform to reveal the underlying mechanisms, such as the altered mechanical sensation in electrical coupling of the heart conduction system and ion channel alternation in relation to altered nuclear architecture, and furthermore to enable screening of drugs that can attenuate this cardiac premature aging phenotype by inhibition of prelamin misfolding and oxidative stress, and also enhancement of autophagy protein clearance and cardiac-protective microRNA.
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China.
authors.forename: Yee-Ki
authors.initials: YK
authors.lastname: Lee
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China.
authors.forename: Xin-Ru
authors.initials: XR
authors.lastname: Ran
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China.
authors.forename: Yee-Man
authors.initials: YM
authors.lastname: Lau
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China.
authors.forename: Kwong-Man
authors.initials: KM
authors.lastname: Ng
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China.
authors.forename: Wing-Hon Kevin
authors.initials: WH
authors.lastname: Lai
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.
authors.forename: Chung-Wah
authors.initials: CW
authors.lastname: Siu
authors.affiliation: Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China. hftse@hkucc.hku.hk.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Guangzhou, People's Republic of China. hftse@hkucc.hku.hk.|Shenzhen Institutes of Research and Innovation, University of Hong Kong, Hong Kong, SAR, China. hftse@hkucc.hku.hk.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D015870:Gene Expression; D042822:Genomic Instability; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011371:Progeria / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D002316:Cardiotonic Agents; C494847:LMNA protein, human; D034904:Lamin Type A
keywords: Cardiovascular diseases; Lamin A/C; Stem cell model; Transgenic mice model