Aging and Mesenchymal Stem Cells: Basic Concepts, Challenges and Strategies

Abstract

Aging and frailty are complex processes implicating multifactorial mechanisms, such as replicative senescence, oxidative stress, mitochondrial dysfunction, or autophagy disorder. All of these mechanisms drive dramatic changes in the tissue environment, such as senescence-associated secretory phenotype factors and inflamm-aging. Thus, there is a demand for new therapeutic strategies against the devastating effects of the aging and associated diseases. Mesenchymal stem cells (MSC) participate in a “galaxy” of tissue signals (proliferative, anti-inflammatory, and antioxidative stress, and proangiogenic, antitumor, antifibrotic, and antimicrobial effects) contributing to tissue homeostasis. However, MSC are also not immune to aging. Three strategies based on MSC have been proposed: remove, rejuvenate, or replace the senescent MSC. These strategies include the use of senolytic drugs, antioxidant agents and genetic engineering, or transplantation of younger MSC. Nevertheless, these strategies may have the drawback of the adverse effects of prolonged use of the different drugs used or, where appropriate, those of cell therapy. In this review, we propose the new strategy of “Exogenous Restitution of Intercellular Signalling of Stem Cells” (ERISSC). This concept is based on the potential use of secretome from MSC, which are composed of molecules such as growth factors, cytokines, and extracellular vesicles and have the same biological effects as their parent cells. To face this cell-free regenerative therapy challenge, we have to clarify key strategy aspects, such as establishing tools that allow us a more precise diagnosis of aging frailty in order to identify the therapeutic requirements adapted to each case, identify the ideal type of MSC in the context of the functional heterogeneity of these cellular populations, to optimize the mass production and standardization of the primary materials (cells) and their secretome-derived products, to establish the appropriate methods to validate the anti-aging effects and to determine the most appropriate route of administration for each case.

Towards the Standardization of Mesenchymal Stem Cell Secretome-Derived Product Manufacturing for Tissue Regeneration

“…This cell-free approach will guide and promote revascularization and endogenous cell homing [ 109 ], with the possibility to specifically orientate tissue regeneration [ 116 ]. The use of MSC-CM is locally applied to reproduce stem cells’ intercellular signaling, in order to reproduce the biological effects of the original cells [ 117 ]. The topical application of a secretome requires a carrier, such as degradable particles, or can be accomplished using a hydrogel.…”

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Ameliorate Aging-Induced BTB Impairment in Porcine Testes by Activating Autophagy and Inhibiting ROS/NLRP3 Inflammasomes via the AMPK/mTOR Signaling Pathway

“…Being small membrane-bound vesicles with a diameter of 30-100 nm, Exos can bind to the recipient cell membrane by virtue of internal membrane contents and deliver a variety of biomolecules (nucleic acids, proteins, lipids, etc.). Although BMSC-derived Exos (BMSC-Exos) have been considered as a promising therapeutic tool for resisting aging [18], the mechanism by which Exos improve the prognosis has not been entirely understood. Thus, the beneficial effect of BMSC-Exos on aging-induced TJ impairment was explored in the present study through both in vitro experiment and mouse model.…”

Reducing oxidative protein folding alleviates senescence by minimizing ER‐to‐nucleus H2O2 release

“…However, the functions of MSCs progressively decline during aging, a process involving lost maintenance of tissue homeostasis, which induces aging‐associated tissue degeneration. (Li et al , 2017; Deng et al , 2019; Fraile et al , 2022; Sun et al , 2022b). Therefore, understanding the molecular processes involved in MSCs senescence is crucial to identify novel therapeutic targets for the treatment of aging‐related degeneration.…”