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

Abstract

Defects in the nuclear lamina occur during physiological aging and as aresult of premature aging disorders. Aging is also accompanied by an increase intranscription of genes encoding cytokines and chemokines, a phenomenon known as thesenescence-associated secretory phenotype (SASP). Progerin and prelamin A triggerpremature 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, weshow that both progerin overexpression and ZMPSTE24 depletion induce paracrinesenescence, especially through the expression of monocyte chemoattractant protein-1(MCP-1), in hMSCs. Importantly, we identified that GATA4 is a mediator regulatingMCP-1 expression in response to prelamin A or progerin in hMSCs.Co-immunoprecipitation revealed that GATA4 expression is maintained due to impairedp62-mediated degradation in progerin-expressing hMSCs. Furthermore, depletion ofGATA4 abrogated SASP-dependent senescence through suppression of NF-ĸB and MCP-1 inhMSCs with progerin or prelamin A. Thus, our findings indicate that abnormal lamin Aproteins trigger paracrine senescence through a GATA4-dependent pathway in hMSCs.This molecular link between defective lamin A and GATA4 can provide insights intophysiological aging and pathological aging disorders.