Chronological Age Affects MSC Senescence In Vitro—A Systematic Review

Abstract

The use of mesenchymal stromal cells (MSCs) in regenerative medicine and tissue engineering is well established, given their properties of self-renewal and differentiation. However, several studies have shown that these properties diminish with age, and understanding the pathways involved are important to provide regenerative therapies in an ageing population. In this PRISMA systematic review, we investigated the effects of chronological donor ageing on the senescence of MSCs. We identified 3023 studies after searching four databases including PubMed, Web of Science, Cochrane, and Medline. Nine studies met the inclusion and exclusion criteria and were included in the final analyses. These studies showed an increase in the expression of p21, p53, p16, ROS, and NF-κB with chronological age. This implies an activated DNA damage response (DDR), as well as increased levels of stress and inflammation in the MSCs of older donors. Additionally, highlighting the effects of an activated DDR in cells from older donors, a decrease in the expression of proliferative markers including Ki67, MAPK pathway elements, and Wnt/β-catenin pathway elements was observed. Furthermore, we found an increase in the levels of SA-β-galactosidase, a specific marker of cellular senescence. Together, these findings support an association between chronological age and MSC senescence. The precise threshold for chronological age where the reported changes become significant is yet to be defined and should form the basis for further scientific investigations. The outcomes of this review should direct further investigations into reversing the biological effects of chronological age on the MSC senescence phenotype.

Curcumin Alleviates the Senescence of Canine Bone Marrow Mesenchymal Stem Cells during In Vitro Expansion by Activating the Autophagy Pathway

“…Organisms continuously repair injured tissues and retard senescence-related processes owing to the distinctively functional characteristics of the MSCs that extensively reside within various tissues and organs [ 15 ]. Unfortunately, age and disease are key factors for MSC senescence in vivo, and internal and external differences in cellular environments accelerate MSC senescence in in vitro culture, both of which negatively affect their capacity for immunosuppression, differentiation, and migration, ultimately reducing the efficacy of self-repair and transplantation in MSCs [ 7 , 14 , 49 , 50 , 51 ]. Oja and colleagues indicated that human BMSCs ceased proliferation at the fifth to ninth passage of clinical-grade cultures and exhibited typical senescence phenotypes, such as a hypertrophic and flat morphology, the activation of cell cycle kinase inhibitors p16 and p21, a decreased proliferation rate, and an enhanced activity of SA-β-gal [ 52 ].…”

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

“…Care would be needed when using ABT-263 in terms of cytotoxic effects; however, when compared with FACS, ABT-263 pretreatment is easy, inexpensive, and requires no special equipment. Senescence of various MSC types is also known to be accelerated during aging of individuals and during in vitro serial passaging of MSCs in culture [ 32 , 37 ]. ABT-263 pretreatment could also be beneficial in these cases.…”

Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities

“…MSC morphological changes, with the increased expression of genes that codify for focal adhesion and actin cytoskeleton organization, have been shown [ 94 ]. A recent systematic review has revealed an increase in SA-βGAL activity in senescent MSCs, particularly in the expression of p53, p21 and p16, Rb, ROS, and NF-κB, together with decreased proliferation markers [ 102 ]. The prolonged expression and activity of any of these regulatory components is sufficient to induce senescence [ 4 ], initially reducing the proliferation rate until the characteristic cell growth arrest of senescent cells is reached [ 70 , 103 , 104 ].…”