Preconditioning with Substance P Restores Therapeutic Efficacy of Aged ADSC by Elevating TNFR2 and Paracrine Potential.

Simple Summary: Stem cell therapy plays a therapeutic role in tissue regeneration in vivo, and its use is increasing for the treatment of incurable diseases. However, stem cells from aged individuals exhibit lower activity, characterized by a high population doubling time and deficient secretion of growth factors. Thus, the transplantation of stem cells with poor activity has shown disappointing results, and we need a strategy to improve the cellular activity of stem cells from aged or diseased individuals. The application of endogenous peptide, substance P, could restore the proliferation rate and paracrine potential of aged stem cells under inflammatory conditions. This suggests the potential use of substance P as a preconditioning factor before stem cell transplantation. Aging leads to a decline in stem cell activity by reducing the repopulation rate and paracrine potential, ultimately diminishing efficacy in vivo. TNF-α can exert inflammatory and cell death actions via Erk by binding to TNFR-1, and survival and tissue repair actions via Akt by binding to TNFR-2. Aged cells are reported to have insufficient expression of TNFR-2, indicating that aged adipose-derived stem cells (ADSCs-E) lack the ability for cell survival and immune control compared to young ADSCs (ADSCs-Y). This study aims to assess the preconditioning effect of SP on the response of ADSCs-E to inflammation. ADSCs-E were treated with SP and then exposed to a high dose of TNF-α for 24 h. Consequently, ADSC-E exhibited weaker viability and lower TNFR2 levels compared to ADSC-Y. In response to TNF-α, the difference in TNFR2 expression became more pronounced in ADSC-E and ADSC-Y. Moreover, ADSC-E showed a severe deficiency in proliferation and paracrine activity. However, preconditioning with SP significantly enhanced the viability of ADSCs-E and also restored TNFR2 expression and paracrine potential, similar to ADSC-Y under inflammatory conditions. Our findings support the idea that preconditioning with SP has the potential to restore the cellular function of senescent stem cells before transplantation. [ABSTRACT FROM AUTHOR]