GATA6 regulates aging of human mesenchymal stem/stromal cells. (30th November 2020)

• Record Type: Journal Article
• Authors: Jiao, Hongli; Walczak, Brian E.; Lee, Ming‐Song; Lemieux, Madeleine E.; Li, Wan‐Ju
• Is Part Of: Stem cells. Volume 39:Number 1(2021)
• Page Start: 62
• Page End: 77
• Publication Date: 2020-11-30
• Subjects: aging -- cell signaling -- mesenchymal stem cells -- reprogramming -- transcription factors; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.3297
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Cellular reprogramming forcing the expression of pluripotency markers can reverse aging of cells, but how molecular mechanisms through which reprogrammed cells alter aging‐related cellular activities still remains largely unclear. In this study, we reprogrammed human synovial fluid‐derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs) using six reprogramming factors and reverted the iPSCs back to MSCs, as an approach to cell rejuvenation. Using the parental and reprogrammed MSCs as control nonrejuvenated and rejuvenated cells, respectively, for comparative analysis, we found that aging‐related activities were greatly reduced in reprogrammed MSCs compared with those in their parental lines, indicating reversal of cell aging. Global transcriptome analysis revealed differences in activities of regulatory networks associated with inflammation and proliferation. Mechanistically, we demonstrated that, compared with control cells, the expression of GATA binding protein 6 (GATA6) in reprogrammed cells was attenuated, resulting in an increase in the activity of sonic hedgehog signaling and the expression level of downstream forkhead box P1 (FOXP1), in turn ameliorating cellular hallmarks of aging. Lower levels of GATA6 expression were also found in cells harvested from younger mice or lower passage cultures. Our findings suggest that GATA6 is a critical regulator increased in aged MSCs that controls the downstream sonic hedgehog signaling and FOXP1 pathway to modulate cellular senescence and aging‐related activities. Abstract : The schema summarizes the GATA6/SHH/FOXP1 mechanism that controls aging‐related changes of biological activities in human mesenchymal stem cells. The reduction of GATA6 expression induced by cellular reprogramming results in an increase in the activity of SHH signaling and FOXP1 expression, which in turn attenuates p53/p21 CIP1 activity, increases proliferation, autophagic activity, and mitochondrial polarization, and promotes chondrogenic/osteogenic differentiation.