*2.4. MSCs' Aging and Mechanosensitivity*

Different age-dependent changes in MSCs were reported, such as decreased proliferation ability [111] and osteogenic differentiation potential [112–114]. Moreover, ageassociated bone loss was linked to the reduced osteogenic potential of MSCs [115]. Aged multipotent progenitor cells lose their sensitivity to alterations in polyacrylamide substrates, while younger multipotent progenitor cells showed a lineage-dependent response to stiffness [116]. The effect of MSCs aging on their mechanosensitivity was investigated by comparing the response of child (11 to 12 years old) and adult MSCs (20–30 years old) to variations in stiffness (10 and 300 kPa) of type I collagen-coated polyacrylamide substrates [117]. Child MSCs revealed more mechanosensitive (increased nuclear-translocation of YAP), improved angiogenesis (enhanced endothelial tubule formation), and osteogenesis (increased alkaline phosphatase activity and mineralization) on stiff substrates as compared to adult MSCs. Based on a customized PCR array, an age-dependent, stiffness-induced upregulation of NOX1, VEGFR1, VEGFR2, WIF1, and JNK3 in child MSCs compared to adults MSCs [117]. Understanding the mechanism behind the age-altered mechanosensitivity of MSCs may open up new avenues to identify potential therapeutic targets to reproduce the enhanced osteogenic and angiogenic potential of adults with bone degeneration and disease.
