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Aging Adipose‐Derived Mesenchymal Stem Cells, Cultured on a Native Young Extracellular Matrix, Are Protected From Senescence and Apoptosis Along With Increased Expression of HLA‐DR and CD74 Associated With PI3K Signaling

Aaron O. Gonzalez,P. A. Abdul Azees,Jerry P Chen,M. Marinković,Brian Cao,Ting Liang,P. Hu,Chih-Ko Yeh,D. D. Dean,Yidong Bai,Xiao-Dong Chen

Published 2025 in Aging Cell

ABSTRACT

Older adults are the primary population for cell‐based therapies for age‐related diseases, but the efficacy of administering autologous mesenchymal stem cells (MSCs) is impaired due to biological aging. In the present study, we cultured aging adipose (AD)‐derived MSCs from > 65‐year‐old donors on extracellular matrix (ECM) synthesized by human amniotic fluid‐derived pluripotent stem cells (ECM Plus) versus tissue culture plastic (TCP) and hypothesized that ECM Plus provided an ideal “young” microenvironment for reactivating and preserving early‐stage progenitor cells within aging AD‐MSCs. To test our hypothesis, we serially sub‐cultured aging AD‐MSCs on ECM Plus or TCP and characterized the cells both phenotypically and functionally, and then analyzed the cells at the single‐cell transcriptomic level for the mechanisms that control cell fate. The results showed that the maintenance of aging AD‐MSCs on ECM Plus significantly restored their quantity and quality. The mechanisms responsible for these effects were associated with a remarkable up‐regulation of intracellular CD74 when cells were maintained on ECM Plus compared to TCP, which triggered activation of the phosphoinositide‐3‐kinase (PI3K) pathway as a key modulator of cell survival (anti‐apoptosis) and suppression of cellular senescence. Moreover, AD‐MSCs maintained on ECM Plus increased their expression of HLA‐DR and stimulated T cell activity. These findings challenge the “immune privilege” of allogeneic MSCs as a universal source for MSC‐based therapies. The present study leads to a new paradigm for treating age‐related diseases: serial administration of rejuvenated autologous MSCs, which may not only replace aged MSCs but also gradually reverse the aged microenvironment.

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