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Research Paper|Volume 4, Issue 11|pp 803—822

Modeling of lamin A/C mutation premature cardiac aging using patient-specific induced pluripotent stem cells

Chung-Wah Siu1,2, Yee-Ki Lee1, Jenny Chung-Yee Ho1,2, Wing-Hon Lai1, Yau-Chi Chan1, Kwong-Man Ng1, Lai-Yung Wong1, Ka-Wing Au1, Yee-Man Lau1, Jinqiu Zhang3, Kenneth Weijian Lay3, Alan Colman3, Hung-Fat Tse1,2
  • 1Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong SAR, China
  • 2Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China
  • 3Institute of Medical Biology, A*STAR Institute of Medical Biology, Singapore

* * Equal contribution

Received: August 1, 2012Accepted: November 28, 2012Published: December 3, 2012
https://doi.org/10.18632/aging.100503

Abstract

AIMS

We identified an autosomal dominant non-sense mutation (R225X) in exon 4 of the lamin A/C (LMNA) gene in a Chinese family spanning 3 generations with familial dilated cardiomyopathy (DCM). In present study, we aim to generate induced pluripotent stem cells derived cardiomyocytes (iPSC-CMs) from an affected patient with R225X and another patient bearing LMNA frame-shift mutation for drug screening.

METHODS and RESULTS

Higher prevalence of nuclear bleb formation and micronucleation was present in LMNAR225X/WT and LMNAFramshift/WT iPSC-CMs. Under field electrical stimulation, percentage of LMNA-mutated iPSC-CMs exhibiting nuclear senescence and cellular apoptosis markedly increased. shRNA knockdown of LMNA replicated those phenotypes of the mutated LMNA field electrical stress. Pharmacological blockade of ERK1/2 pathway with MEK1/2 inhibitors, U0126 and selumetinib (AZD6244) significantly attenuated the pro-apoptotic effects of field electric stimulation on the mutated LMNA iPSC-CMs.

CONCLUSION

LMNA-related DCM was modeled in-vitro using patient-specific iPSC-CMs. Our results demonstrated that haploinsufficiency due to R225X LMNA non-sense mutation was associated with accelerated nuclear senescence and apoptosis of iPSC- CMs under electrical stimulation, which can be significantly attenuated by therapeutic blockade of stress-related ERK1/2 pathway.