Mesenchymal Stem/Stromal Cell Senescence: Hallmarks, Mechanisms, and Combating Strategies

Abstract

Aging is a multifaceted and complicated process, manifested by a decline of normal physiological functions across tissues and organs, leading to overt frailty, mortality, and chronic diseases, such as skeletal, cardiovascular, and cognitive disorders, necessitating the development of practical therapeutic approaches. Stem cell aging is one of the leading theories of organismal aging. For decades, mesenchymal stem/stromal cells (MSCs) have been regarded as a viable and ideal source for stem cell-based therapy in anti-aging treatment due to their outstanding clinical characteristics, including easy accessibility, simplicity of isolation, self-renewal and proliferation ability, multilineage differentiation potentials, and immunomodulatory effects. Nonetheless, as evidenced in numerous studies, MSCs undergo functional deterioration and gradually lose stemness with systematic age in vivo or extended culture in vitro, limiting their therapeutic applications. Even though our understanding of the processes behind MSC senescence remains unclear, significant progress has been achieved in elucidating the aspects of the age-related MSC phenotypic changes and possible mechanisms driving MSC senescence. In this review, we aim to summarize the current knowledge of the morphological, biological, and stem-cell marker alterations of aging MSCs, the cellular and molecular mechanisms that underlie MSC senescence, the recent progress made regarding the innovative techniques to rejuvenate senescent MSCs and combat aging, with a particular focus on the interplay between aging MSCs and their niche as well as clinical translational relevance. Also, we provide some promising and novel directions for future research concerning MSC senescence.

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

“…Particular attention was paid to the introduction of mes-2 of 22 enchymal stromal stem cells (MSC) into an organism experiencing problems caused by organ dysfunction as a result of physiological, (e.g., ischemia of different origin), chemical (drugs, poisons), biological (bacterial or viral invasion) or physical (hyperthermia, trauma) challenge. Admittedly, fetal MSC have the greatest therapeutic activity with an obvious loss of therapeutic properties as the host organism from which the MSC were isolated ages [1,2]. However, in any case, a serious limitation is the source of MSC and what is also important, obtaining it in an amount sufficient to afford the therapeutic effect, and this problem has not yet found a proper solution.…”

Paracrine Senescence of Mesenchymal Stromal Cells Involves Inflammatory Cytokines and the NF-κB Pathway

“…Numerous studies have shown that senescence is associated with increased production of pro-inflammatory cytokines, such as IL-1 and IL-8, by senescent cells, collectively referred to as pro-inflammatory-associated SASP [ 34 ]. Notably, it is now evident that senescence can be transmitted to normal cells by SASP in a paracrine or autocrine manner [ 35 ].…”

“…The senescent state is primarily characterized by durable cell cycle arrest [ 34 , 38 ]. Activation of cyclin-dependent kinase (CDK) inhibitors p16 and p21 is essential for senescence-associated growth arrest, which antagonizes CDK to block cell cycle progression [ 34 , 38 ].…”

“…The senescent state is primarily characterized by durable cell cycle arrest [ 34 , 38 ]. Activation of cyclin-dependent kinase (CDK) inhibitors p16 and p21 is essential for senescence-associated growth arrest, which antagonizes CDK to block cell cycle progression [ 34 , 38 ]. During cellular senescence, the expression level of p16 and p21 was shown to be upregulated both in vitro and in vivo, elevating SA-β-gal expression [ 6 ].…”

Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting

“…On the other hand, oxidative stress, a higher rate of oxygen consumption, and genomic instability were all linked to MSC senescence. Thus, assessment of MSCs for percentage of aneuploidy cells before using them in clinical applications is recommended to decide how to combat MSC senescence [54,55]. Also, in vitro propagation of MSCs attenuates their capacity for cartilage regeneration ability and presents chromosomal morphological changes associated with potential anomalous karyotypes, which accelerate premature senescence [56].…”