Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development

Abstract

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.

Subchondral bone microenvironment in osteoarthritis and pain

“…p16 INK4a -positive senescent MSCs have been identified in subchondral bone trabeculae in an anterior cruciate ligament transection (ACLT)-induced OA model, as well as in an aging mouse model (19–20 months old) 142 and a spontaneous OA mouse model. 143 Senescence-associated phenotypical features of MSCs are observed in subchondral bone in OA, including G0/G1-phase stagnation, increased β-gal expression, and decreased S-phase entry. 144 …”

Down-Regulated Exosomal MicroRNA-221 – 3p Derived From Senescent Mesenchymal Stem Cells Impairs Heart Repair

“…In addition, in vitro amplification of MSCs is necessary prior to their clinical application and inevitably leads to replicative aging process (Mathiasen et al, 2015;Guijarro et al, 2016). Accumulating evidence shows that aging affects the functions of MSCs, including differentiation, proliferation and migration, as well as angiogenic potential, and in turn reduces their clinical efficacy (Malaise et al, 2019;Zhang et al, 2019;Wang et al, 2020). There is an urgent need to explore strategies that will enable functional recovery of elderly MSCs.…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…MSC aging was also correlated to impaired hematopoietic functions: BM-MSCs (fundamental for the maintenance of the hematopoietic stem cell compartment in the bone marrow) from aged donors were shown to activate a SASP-like program contributing to young HSCs functional impairment by promoting an inflammatory state in HSCs [119]. Senescence of synovial and subchondral BM-MSCs is likely to contribute to joint alteration and osteoarthritis (OA) development: this was shown in vitro and in vivo with p16-positive human MSCs co-cultured with OA chondrocytes or intra-articularly injected in young mice [120]. BM-MSC number was reduced in adulthood compared to childhood together with an increase of senescence markers (ROS, p21, p53) [121].…”