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.

Keywords: cell signaling; mesenchymal stem/stromal cells; mitochondrial dysfunction; reactive oxygen species (ROS); rejuvenation; senescence; stem cell niche.

Mesenchymal stem/stromal cell (MSC) senescence is manifested by distinctive phenotypic changes, including flattened and enlarged cell morphology, SASP, biomarker changes, telomere attrition, epigenetic alterations, impaired differentiation potential, and declines in proliferation ability. Abbreviations: MSC, mesenchymal stem/stromal cell; RUNX2, runt-related transcription factor 2; PPAR-γ, peroxisome proliferator-activated receptor-γ; SASP, senescence-associated secretory phenotype; IL-6/8, interleukin-6/8; SA-β-gal, senescence-associated beta-galactosidase; pRB, phosphorylated retinoblastoma.

Figure 1.

DNA damage response network in MSC cell cycle arrest. DNA damage response is triggered by endogenous and exogenous stresses in senescent MSCs, such as ROS, telomere attrition, oncogene activation, and irradiation, resulting in activation of the 2 main senescence-related signaling pathways, namely p53/p21^CIP1/WAF1 and p16^INK4A, which leads to cell cycle arrest and MSC senescence. Abbreviations: DDR, DNA damage response; ROS, reactive oxygen species; MSC, mesenchymal stem/stromal cell; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homolog; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; MLK3, mixed lineage kinase 3; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; MEKK, MAPK kinase kinase; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia mutated and RAD3 related; MDM2, monocyte-derived macrophages-2; CDK, cyclin-dependent kinase.

Figure 2.

Mitochondrial dysfunction in MSC senescence. Senescence-associated mitochondrial dysfunction is one of the hallmarks of MSC aging, including dysregulated mitochondrial biogenesis, decreased mitophagy, and hyper-fused mitochondrial networks. During aging, AMP/ATP and NAD+/NADH ratios are metabolically disturbed, initiating downstream signaling cascades. Of note, excessive ROS generated by dysfunctional mitochondria may cause DNA damage and ROS accumulation, which in turn exacerbates mitochondrial function, forming a positive feedback loop. Abbreviations: ETC, electron transport chain; NADH, reduced nicotinamide adenine dinucleotide; NAD+, oxidized nicotinamide adenine dinucleotide; ADP, adenosine diphosphate; ATP, adenosine triphosphate; AMPK, 5ʹ-AMP-activated protein kinase; PGC-1α/β, proliferator-activated receptor-gamma coactivator-1α/β; MiDAS, mitochondrial dysfunction-associated senescence.

Figure 3.

The interplay between senescent MSCs and their niche. MSCs are resident in a supportive microenvironment termed stem cell niche. The stem cell niche contains multiple types of cells, vascular networks, secreted metabolic and physical factors, and ECM. On the one hand, resident MSCs are profoundly affected by their niche. On the other hand, secretome changes of senescent MSCs, such as SASP-related factors, result in stem cell niche remodeling and creating a pro-inflammatory milieu. Abbreviations: ECM, extracellular matrix; SASP, senescence-associated secretory phenotype; NK cell, natural killer cell; HSC, hematopoietic stem cell; WNT, Wnt/β-catenin; TGF-β, transforming growth factor-β; IGF-1, insulin growth factor-1; DPP-4, dipeptidyl peptidase-4; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; BMP, bone morphogenetic protein.