Research Paper|Volume 12, Issue 2|pp 1987—2004

Paracrine senescence of human endometrial mesenchymal stem cells: a role for the insulin-like growth factor binding protein 3

Irina Vassilieva¹, Vera Kosheverova¹, Mikhail Vitte¹, Rimma Kamentseva¹, Alla Shatrova¹, Natalia Tsupkina¹, Elena Skvortsova¹, Aleksandra Borodkina¹, Elena Tolkunova¹, Nikolay Nikolsky¹, Elena Burova¹

¹Department of Intracellular Signaling and Transport, Institute of Cytology of the Russian Academy of Sciences, St. Petersburg 194064, Russia

Received: November 19, 2019Accepted: January 2, 2020Published: January 17, 2020

https://doi.org/10.18632/aging.102737

Copyright: © 2020 Vassilieva et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Stress-induced premature cell senescence is well recognized to be accompanied by emerging the senescence-associated secretory phenotype (SASP). Secreted SASP factors can promote the senescence of normal neighboring cells through autocrine/paracrine pathways and regulate the senescence response, as well. Regarding human endometrium-derived mesenchymal stem cells (MESCs), the SASP regulation mechanisms as well as paracrine activity of senescent cells have not been studied yet. Here, we examined the role of insulin-like growth factor binding protein 3 (IGFBP3) in the paracrine senescence induction in young MESCs. The H₂O₂-induced premature senescence of MESCs led to increased IGFBP3 in conditioned media (CM). The inhibitory analysis of both MAPK and PI3K signaling pathways showed that IGFBP3 releasing from senescent cells is mainly regulated by PI3K/Akt pathway activity. IGFBP3 appears to be an important senescence-mediating factor as its immunodepletion from the senescent CM weakened the pro-senescent effect of CM on young MESCs and promoted their growth. In contrast, young MESCs acquired the senescence phenotype in response to simultaneous addition of recombinant IGFBP3 (rIGFBP3). The mechanism of extracellular IGFBP3 internalization was also revealed. The present study is the first to demonstrate a significant role of extracellular IGFBP3 in paracrine senescence induction of young MESCs.