GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging

Cited 29 time in Web of Science Cited 30 time in Scopus

Lee, Jin Young; Yu, Kyung-Rok; Lee, Byung-Chul; Kang, Insung; Kim, Jae-Jun; Jung, Eui-Jung; Kim, Hyung-Sik; Seo, Yoojin; Choi, Soon Won; Kang, Kyung-Sun

Issue Date
Experimental and Molecular Medicine, Vol.50 No.5, p. 63
Defects in the nuclear lamina occur during physiological aging and as a result of premature aging disorders. Aging is also accompanied by an increase in transcription of genes encoding cytokines and chemokines, a phenomenon known as the senescence-associated secretory phenotype (SASP). Progerin and prelamin A trigger premature senescence and loss of function of human mesenchymal stem cells (hMSCs), but little is known about how defects in nuclear lamin A regulate SASP. Here, we show that both progerin overexpression and ZMPSTE24 depletion induce paracrine senescence, especially through the expression of monocyte chemoattractant protein-1 (MCP-1), in hMSCs. Importantly, we identified that GATA4 is a mediator regulating MCP-1 expression in response to prelamin A or progerin in hMSCs. Co-immunoprecipitation revealed that GATA4 expression is maintained due to impaired p62-mediated degradation in progerin-expressing hMSCs. Furthermore, depletion of GATA4 abrogated SASP-dependent senescence through suppression of NF-kappa B and MCP-1 in hMSCs with progerin or prelamin A. Thus, our findings indicate that abnormal lamin A proteins trigger paracrine senescence through a GATA4-dependent pathway in hMSCs. This molecular link between defective lamin A and GATA4 can provide insights into physiological aging and pathological aging disorders.
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Journal Papers (저널논문_수의학과)
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