Research Paper Volume 11, Issue 20 pp 9128—9146
Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development
- 1 IRMB, University Montpellier, INSERM, Montpellier, France
- 2 GIGA Research, CHU of Liège and University of Liège, Liège, Belgium
- 3 Clinic for Orthopedics and Traumatology, University Hospital of Basel, Basel, Switzerland
- 4 Hôpital Lapeyronie, Clinical immunology and Osteoarticular Diseases Therapeutic Unit, Montpellier, France
- 5 Trauma Department, Hannover Medical School, Hannover, Germany
- 6 INM, University Montpellier, INSERM, Montpellier, France
received: July 10, 2019 ; accepted: October 14, 2019 ; published: October 22, 2019 ;https://doi.org/10.18632/aging.102379
How to Cite
Copyright © 2019 Malaise et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Tissue accumulation of p16INK4a-positive senescent cells is associated with age-related disorders, such as osteoarthritis (OA). These cell-cycle arrested cells affect tissue function through a specific secretory phenotype. The links between OA onset and senescence remain poorly described. Using experimental OA protocol and transgenic Cdkn2a+/luc and Cdkn2aluc/luc mice, we found that the senescence-driving p16INK4a is a marker of the disease, expressed by the synovial tissue, but is also an actor: its somatic deletion partially protects against cartilage degeneration. We test whether by becoming senescent, the mesenchymal stromal/stem cells (MSCs), found in the synovial tissue and sub-chondral bone marrow, can contribute to OA development. We established an in vitro p16INK4a-positive senescence model on human MSCs. Upon senescence induction, their intrinsic stem cell properties are altered. When co-cultured with OA chondrocytes, senescent MSC show also a seno-suppressive properties impairment favoring tissue degeneration. To evaluate in vivo the effects of p16INK4a-senescent MSC on healthy cartilage, we rely on the SAMP8 mouse model of accelerated senescence that develops spontaneous OA. MSCs isolated from these mice expressed p16INK4a. Intra-articular injection in 2-month-old C57BL/6JRj male mice of SAMP8-derived MSCs was sufficient to induce articular cartilage breakdown. Our findings reveal that senescent p16INK4a-positive MSCs contribute to joint alteration.