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

Experimental & Molecular Medicine
Jin Young LeeKyung-Sun Kang

Abstract

Defects in the nuclear lamina occur during physiological aging and as. result of premature aging disorders. Aging is also accompanied by an increase in transcription of genes encoding cytokines and chemokines,. phenomenon known as the senescence-associated secretory phenotype (SASP). Progerin and prelamin. trigger premature senescence and loss of function of human mesenchymal stem cells (hMSCs), but little is known about how defects in nuclear lamin. 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. mediator regulating MCP-1 expression in response to prelamin. 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-ĸB and MCP-1 in hMSCs with progerin or prelamin A. Thus, our findings indicate that abnormal lamin. proteins trigger paracrine senescence through. GATA4-dependent pathway in hMSCs. This molecular link between defective lamin. a...Continue Reading

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Citations

Feb 27, 2019·Current Osteoporosis Reports·Robert J PignoloAbhishek Chandra
Aug 31, 2019·Aging·Daniel Moreno-BlasSusana Castro-Obregón
Feb 27, 2020·Biomolecules·Simona Neri, Rosa Maria Borzì
Jun 11, 2019·Oxidative Medicine and Cellular Longevity·Xin LiYuelin Zhang
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May 25, 2020·Ageing Research Reviews·Vittoria CenniGiovanna Lattanzi

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Methods Mentioned

BETA
transfection
PCR
ELISA
co-immunoprecipitation
co-IP
light microscopy

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