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

Abstract

Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.

Keywords: Aging; Cellular senescence; Differentiation; Mesenchymal stem cell; Senescence markers; Anti-cellular senescence.

Fig. 1

Major contributors to aging machinery. The nine hallmarks of aging: DNA damage, telomere attrition, epigenetic alteration, loss of proteostasis, mitochondrial dysfunction, cellular senescence, nutrient sensing, intracellular communication, and stem cell exhaustion [34]

Fig. 2

Overview of MSC senescence homeostasis. Signaling pathways, AMPK, sirtuins, Nrf2, and Hedgehog induce antisenescence effects (green), whereas signaling pathways, mTOR, ROS, IGF1, and NF-κB activate senescence (red) in MSCs. Genomic instability, telomere attrition, epigenetic alteration, mitochondrial dysfunction, and failed proteostasis induce MSC senescence

Fig. 3

The major intracellular signaling pathways in cellular senescence and differentiation  of MSCs. AMPK, sirtuins, Nrf2, and Hedgehog work as promoters for MSC immortalization and osteogenic differentiation (green); however, ROS, mTOR, and IGF1 are considered as inducers of MSC aging and adipogenic differentiation (red). Activate ( ), inhibit ( )

Fig. 4

Overview of replicative senescence markers in MSCs. The major markers of MSC aging in laboratory are DNA damage, P53 upregulation,  SA-β-gal expression, morphological changes, cell-cycle arrest, skewed differentiation, induced SASP, and compromised colony-forming ability. Activate ( )

Fig. 5

Concept of young MSCs versus senescent MSCs, showing the major cellular and organellar differences between normal and senescent MSCs. Senescent MSCs contain more damaged DNA and proteins, stressed organelles, short telomeres, and induced ROS

Fig. 6

Lifestyle modifications and pharmacological interventions are strategies to combat aging and cellular senescence. Optimizing lifestyle with appropriate diet, exercise, sleep, and no smoking and pollution is critical to avoiding aging and cellular senescence. Pharmacological interventions by metformin, resveratrol, curcumin, statins, antioxidants, mTOR inhibitors, sirtuins activators, caloric restriction mimetics, and probiotics are also suggested as anti-aging remedies. Activate, inhibit

Fig. 7

Nutraceutical intervention as a strategy to combat cellular senescence. Flavonoids, nonflavonoids, and other nutraceuticals compromise cellular senescence through regulating ROS, inflammation, SASP, p53, p21, and PPARγ. Activate, inhibit, nutraceuticals (bold)

Fig. 8

Senolysis as a strategy to combat cellular senescence. Indicated senolytics induce cellular rejuvenation through targeting anti-apoptotic pathways, and PI3K/Akt, p53, NF-κB, and JAK signaling pathways. Activate, inhibit, senolytics (bold)