Clearance of senescent cells with ABT-263 improves biological functions of synovial mesenchymal stem cells from osteoarthritis patients

Abstract

Background Osteoarthritis (OA) is an age-related joint disease characterized by progressive cartilage loss. Synovial mesenchymal stem cells (MSCs) are anticipated as a cell source for OA treatment; however, synovial MSC preparations isolated from OA patients contain many senescent cells that inhibit cartilage regeneration through their senescence-associated secretory phenotype (SASP) and poor chondrogenic capacity. The aim of this study was to improve the biological function of OA synovial MSCs by removing senescent cells using the senolytic drug ABT-263. Methods We pretreated synovial MSCs derived from 5 OA patients with ABT-263 for 24 h and then evaluated senescence-associated beta-galactosidase (SA-β-gal) activity, B cell lymphoma 2 (BCL-2) activity, apoptosis, surface antigen expression, colony formation ability, and multipotency. Results The ABT-263 pretreatment significantly decreased the percentage of SA-β-gal-positive cells and BCL-2 expression and induced early- and late-stage apoptosis. Cleaved caspase-3 was expressed in SA-β-gal-positive cells. The pretreated MSCs formed greater numbers of colonies with larger diameters. The expression rate of CD34 was decreased in the pretreated cells. Differentiation assays revealed that ABT-263 pretreatment enhanced the adipogenic and chondrogenic capabilities of OA synovial MSCs. In chondrogenesis, the pretreated cells produced greater amounts of glycosaminoglycan and type II collagen and showed lower expression of senescence markers (p16 and p21) and SASP factors (MMP-13 and IL-6) and smaller amounts of type I collagen. Conclusion Pretreatment of synovial MSCs from OA patients with ABT-263 can improve the function of the cells by selectively eliminating senescent cells. These findings indicate that ABT-263 could hold promise for the development of effective cell-based OA therapy.

Mesenchymal Stem Cell Senescence during Aging:From Mechanisms to Rejuvenation Strategies

“…There are many senescent cells in synovial MSC preparations obtained from patients with osteoarthritis (OA). Pretreatment with ABT-263 significantly reduced SA-β-gal-positive cells and Bcl-2 expression and improved the function of MSCs [164].…”

Excessive sulfur oxidation in endoplasmic reticulum drives an inflammatory reaction of chondrocytes in aging mice

“…At present, there are many studies on aging and osteoarthritis, ranging from the RNA level to the protein level. Based on existing studies (Liu et al, 2021), (Miura et al, 2022) , (Varela-Eirín et al, 2022), this study found that with the increase of age, the number of aging cells in articular cartilage increased, which promoted the occurrence of inflammatory aging-related secretory phenotype (SASP), and then led to an increase in the expression of inflammatory response-related genes and proteins. At the same time, it has been reported that osteoarthritis is related to bone metabolism.…”

Senotherapeutics and Their Molecular Mechanism for Improving Aging

“…ABT-263 also rejuvenated aged hematopoietic stem cells and muscle stem cells by clearing senescent cells ( Chang et al ., 2016 ). By binding the inhibitory domain of anti-apoptotic Bcl-2 and Bcl-xL, ABT-263 specifically eliminated both senescent muscle stem cells (MuSCs) and senescent bone marrow hematopoietic stem cells (HSCs) and eventually contributed to the amelioration or rejuvenation of MuSCs and HSCs in aged mice ( Miura et al ., 2022 ). In addition, ABT-263 cleared senescent foam cell macrophages in atherosclerotic lesions, preventing atherosclerosis progression in LDLR −/− mice ( Garrido et al ., 2022 ).…”