Restoring extracellular matrix synthesis in senescent stem cells

Abstract

Collagen type III (COL3) is one of the 3 major collagens in the body, and loss of expression or mutations in the COL3 gene have been associated with the onset of vascular diseases such the Ehlers‐Danlos syndrome. Previous work reported a significant reduction of COL3 in tissues such as skin and vessels with aging. In agreement, we found that COL3 was significantly reduced in senescent human mesenchymal stem cells and myofibroblasts derived from patients with Hutchinson‐Gilford progeria syndrome, a premature aging syndrome. Most notably, we discovered that ectopic expression of the embryonic transcription factor Nanog homeobox (NANOG) restored COL3 expression by restoring the activity of the TGF‐β pathway that was impaired in senescent cells. RNA sequencing analysis showed that genes associated with the activation of the TGF‐β pathway were up‐regulated, whereas negative regulators of the pathway were down‐regulated upon NANOG expression. Chromatin immunoprecipitation sequencing and immunoprecipitation experiments revealed that NANOG bound to the mothers against decapentaplegic (SMAD)2 and SMAD3 promoters, in agreement with increased expression and phosphorylation levels of both proteins. Using chemical inhibition, short hairpin RNA knockdown, and gain of function approaches, we established that both SMAD2 and SMAD3 were necessary to mediate the effects of NANOG, but SMAD3 overexpression was also sufficient for COL3 production. In summary, NANOG restored production of COL3, which was impaired by cellular aging, suggesting novel strategies to restore the impaired extracellular matrix production and biomechanical function of aged tissues, with potential implications for regenerative medicine and anti‐aging treatments.—Rong, N., Mistriotis, P., Wang, X., Tseropoulos, G., Rajabian, N., Zhang, Y., Wang, J., Liu, S., Andreadis, S. T. Restoring extracellular matrix synthesis in senescent stem cells. FASEB J. 33, 10954–10965 (2019). http://www.fasebj.org

Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges

“…A feedback loop likely exists between PBX1 and AKT signaling, maintaining HF-MSCs in a highly proliferative state with differentiation potential (Liu, 2019). NANOG also restores expression of COL3 and thus stabilizes extracellular matrix synthesis (Rong, 2019).…”

Epigenetic Clock and Circadian Rhythms in Stem Cell Aging and Rejuvenation

“…A feedback loop likely exists between PBX1 and AKT signaling, keeping MSCs in a highly proliferative state with good differentiation potential [245]. NANOG also restores COL3 expression and thus stabilizes extracellular matrix synthesis [247]. The use of ESC-Exos has also been shown to rejuvenate endothelial cells, enhance angiogenesis, reduce ROS levels, and promote pressure ulcer regeneration in aging mice [248,249].…”

Epigenetic Clock, Circadian Rhythms and Cell Aging

“…[245]. NANOG also restores COL3 expression and thus stabilizes extracellular matrix synthesis [247]. The use of ESC-Exos has also been shown to rejuvenate endothelial cells, enhance angiogenesis, reduce ROS levels, and promote pressure ulcer regeneration in aging mice [248,249].…”