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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01659

The upregulation of Toll-like receptor 3 via autocrine IFN-beta signaling drives the senescence of human mesenchymal stem cells through JAK1

  • 1College of Medicine, University of Ulsan, South Korea
  • 2University of Ulsan College of Medicine , Ulsan , South Korea, South Korea
  • 3University of Ulsan College of Medicine , Ulsan , South Korea , Seoul , South Korea, South Korea

Although mesenchymal stromal cells (MSCs) are among the most promising cell sources for cell-based therapies and regenerative medicine, the decline in their function with age due to cellular senescence limits their therapeutic applications. Unveiling the underlying mechanism of MSC senescence is therefore of substantial interest with regard to advancing MSC-based cell therapies. We here show that the induction of human MSC senescence causes the predominant upregulation of Toll-like receptor 3 (TLR3). Subsequent TLR3 activation by polyinosinic-polycytidylic acid triggers the prominent features of senescence. Using a clustered regularly interspaced short palindromic repeats/Cas9 library screening system, we identified Janus kinase 1 (JAK1) as the candidate regulatory factor for TLR3-mediated MSC senescence. A JAK1 deficiency blocked the MSC senescence phenotype upon TLR3 activation and TLR3 induction. Targeting the JAK1 pathway using chemical JAK1 inhibitors also significantly suppressed TLR3-mediated MSC senescence. Importantly, we further observed that MSC senescence is driven by a senescence-associated secretory phenotype (SASP) and that interferon-beta (IFN-beta) is therefore a component of TLR3-dependent SASP, whereby its autocrine actions upregulate TLR3 and suppress cell proliferation. A JAK1 depletion significantly interrupted these effects of IFN- beta, indicating that JAK1 is a signaling mediator linking IFN- beta activity to TLR3 expression and the process of MSC senescence. Collectively, our findings provide new mechanistic insights into MSC senescence by revealing the role of an autocrine regulatory loop of SASP evoked by TLR3 activation.

Keywords: Mesenchymal stromal cell, Toll-Like Receptor 3, senescence, Janus Kinase 1, Interferon-beta

Received: 25 Mar 2019; Accepted: 03 Jul 2019.

Edited by:

Silvano Sozzani, University of Brescia, Italy

Reviewed by:

Tiziana Musso, University of Turin, Italy
Chiara Palmi, Fondazione Matilde Tettamanti Menotti De Marchi, Italy  

Copyright: © 2019 Chang, Lee, Choi, Kim, Lee, Jin, Lee and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mx. Eun-Ju Chang, College of Medicine, University of Ulsan, Ulsan, South Korea,
Mx. Seong Who Kim, University of Ulsan College of Medicine , Ulsan , South Korea, Seoul, South Korea,