Sprouty1 Prevents Cellular Senescence Maintaining Proliferation and Differentiation Capacity of Human Adipose Stem/Progenitor Cells. (18th April 2020)

• Record Type: Journal Article
• Authors: Mandl, Markus; Wagner, Sonja A; Hatzmann, Florian M; Ejaz, Asim; Ritthammer, Heike; Baumgarten, Saphira; Viertler, Hans P; Springer, Jochen; Zwierzina, Marit E; Mattesich, Monika; Brucker, Camille; Waldegger, Petra; Pierer, Gerhard; Zwerschke, Werner
• Editors: Le Couteur, David
• Is Part Of: Journals of gerontology. Volume 75:Number 12(2020)
• Page Start: 2308
• Page End: 2319
• Publication Date: 2020-04-18
• Subjects: Adipogenesis -- Adipose stem cell -- Obesity -- Senescence -- Sprouty1; Geriatrics -- Periodicals; Gerontology -- Periodicals; 618.97
• DOI: 10.1093/gerona/glaa098
• Languages: English
• ISSNs: 1079-5006

Abstract

Abstract: The role of Ras-Mitogen-activated protein kinase (MAPK) signaling in cellular aging is not precisely understood. Recently, we identified Sprouty1 ( SPRY1 ) as a weight-loss target gene in human adipose stem/progenitor cells (ASCs) and showed that Sprouty1 is important for proper regulation of adipogenesis. In the present study, we show that loss-of-function of Sprouty1 by CRISPR/Cas9-mediated genome editing in human ASCs leads to hyper-activation of MAPK signaling and a senescence phenotype. Sprouty1 knockout ASCs undergo an irreversible cell cycle arrest, become enlarged and stain positive for senescence-associated β-galactosidase. Sprouty1 down-regulation leads to DNA double strand breaks, a considerably increased number of senescence-associated heterochromatin foci and induction of p53 and p21 Cip1 . In addition, we detect an increase of hypo-phosphorylated Retinoblastoma (Rb) protein in SPRY1 knockout ASCs. p16 Ink4A is not induced. Moreover, we show that Sprouty1 knockout leads to induction of a senescence-associated secretory phenotype as indicated by the activation of the transcription factors NFκB and C/EBPβ and a significant increase in mRNA expression and secretion of interleukin-8 (IL-8) and CXCL1/GROα. Finally, we demonstrate that adipogenesis is abrogated in senescent SPRY1 knockout ASCs. In conclusion, this study reveals a novel mechanism showing the importance of Sprouty1 for the prevention of senescence and the maintenance of the proliferation and differentiation capacity of human ASCs.