PMID- 29760459 OWN - NLM STAT- MEDLINE DCOM- 20190318 LR - 20200306 IS - 2092-6413 (Electronic) IS - 1226-3613 (Print) IS - 1226-3613 (Linking) VI - 50 IP - 5 DP - 2018 May 14 TI - GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A-mediated human mesenchymal stem cell aging. PG - 1-12 LID - 10.1038/s12276-018-0092-3 [doi] LID - 63 AB - 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-kB 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. and GATA4 can provide insights into physiological aging and pathological aging disorders. FAU - Lee, Jin Young AU - Lee JY AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. FAU - Yu, Kyung-Rok AU - Yu KR AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. AD - Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA. FAU - Lee, Byung-Chul AU - Lee BC AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. FAU - Kang, Insung AU - Kang I AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. FAU - Kim, Jae-Jun AU - Kim JJ AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. FAU - Jung, Eui-Jung AU - Jung EJ AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. FAU - Kim, Hyung-Sik AU - Kim HS AD - Pusan National University School of Medicine, Busan, 49241, Republic of Korea. AD - Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Republic of Korea. FAU - Seo, Yoojin AU - Seo Y AD - Pusan National University School of Medicine, Busan, 49241, Republic of Korea. AD - Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Republic of Korea. FAU - Choi, Soon Won AU - Choi SW AUID- ORCID: 0000-0001-8642-6093 AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. FAU - Kang, Kyung-Sun AU - Kang KS AD - Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea. kangpub@snu.ac.kr. AD - College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea. kangpub@snu.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180514 PL - United States TA - Exp Mol Med JT - Experimental & molecular medicine JID - 9607880 RN - 0 (Chemokine CCL2) RN - 0 (GATA4 Transcription Factor) RN - 0 (Lamin Type A) RN - 0 (prelamin A) SB - IM MH - *Cellular Senescence MH - Chemokine CCL2/*metabolism MH - DNA Damage MH - Down-Regulation MH - GATA4 Transcription Factor/*metabolism MH - Humans MH - Lamin Type A/*metabolism MH - Mesenchymal Stem Cells/*cytology/*metabolism MH - Models, Biological MH - Umbilical Cord/cytology PMC - PMC5951912 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/05/16 06:00 MHDA- 2019/03/19 06:00 PMCR- 2018/05/14 CRDT- 2018/05/16 06:00 PHST- 2017/09/29 00:00 [received] PHST- 2018/03/08 00:00 [accepted] PHST- 2018/02/12 00:00 [revised] PHST- 2018/05/16 06:00 [entrez] PHST- 2018/05/16 06:00 [pubmed] PHST- 2019/03/19 06:00 [medline] PHST- 2018/05/14 00:00 [pmc-release] AID - 10.1038/s12276-018-0092-3 [pii] AID - 92 [pii] AID - 10.1038/s12276-018-0092-3 [doi] PST - epublish SO - Exp Mol Med. 2018 May 14;50(5):1-12. doi: 10.1038/s12276-018-0092-3.