Dataset Information

Senescence of donor cells impairs fat graft regeneration by suppressing adipogenesis and increasing expression of senescence-associated secretory phenotype factors.

ABSTRACT:

Background

Fat grafting has been regarded as a promising approach for regenerative therapy. Given the rapidly aging population, better understanding of the effect of age on fat graft outcomes and the underlying mechanisms is urgently needed.

Methods

C57/BL6 mice [old (O, 18-20-month-old) and young (Y, 4-month-old)] were randomized to four fat graft groups [old-to-old (O-O), young-to-young (Y-Y), old-to-young (O-Y), and young-to-old (Y-O)]. Detailed cellular events before and after grafting were investigated by histological staining, RNA sequencing, and real-time polymerase chain reaction. The adipogenic differentiation potential of adipose-derived mesenchymal stem cells (AD-MSCs) from old or young donors was investigated in vitro. Additionally, adipogenesis of AD-MSCs derived from old recipients was evaluated in the culture supernatant of old or young donor fat tissue.

Results

After 12 weeks, the volume of fat grafts did not significantly differ between the O-O and O-Y groups or between the Y-Y and Y-O groups, but was significantly smaller in the O-O group than in the Y-O group and in the O-Y group than in the Y-Y group. Compared with fat tissue from young mice, senescence-associated secretory phenotype (SASP) factors were upregulated in fat tissue from old mice. Compared with the Y-O group, adipogenesis markers were downregulated in the O-O group, while SASP factors including interleukin (IL)-6, tumor necrosis factor-α, and IL-1β were upregulated. In vitro, AD-MSCs from old donors showed impaired adipogenesis compared with AD-MSCs from young donors. Additionally, compared with the culture supernatant of young donor fat tissue, the culture supernatant of old donor fat tissue significantly decreased adipogenesis of AD-MSCs derived from old recipients, which might be attributable to increased levels of SASP factors.

Conclusions

Age has detrimental effects on fat graft outcomes by suppressing adipogenesis of AD-MSCs and upregulating expression of SASP factors, and fat graft outcomes are more dependent on donor age than on recipient age. Thus, rejuvenating fat grafts from old donors or banking younger adipose tissue for later use may be potential approaches to improve fat graft outcomes in older adults.

SUBMITTER: Chen X

PROVIDER: S-EPMC8164816 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background and objectivesSmall donor and/or kidney sizes relative to recipient size are associated with a higher risk of kidney allograft failure. Donor and recipient ages are associated with graft survival and may modulate the relationship between size mismatch and the latter. The aim of this study was to determine whether the association between donor-recipient size mismatch and graft survival differs by donor and recipient age.Design, setting, participants, & measurementWe performed a retrospective cohort study of first adult deceased donor kidney transplantations performed between 2000 and 2018 recorded in the Scientific Registry of Transplant Recipients. We used multivariable Cox proportional hazards models to assess the association between donor-recipient body surface area ratio and death-censored graft survival, defined as return to dialysis or retransplantation. We considered interactions between donor-recipient body surface area ratio and each of recipient and donor age.ResultsAmong the 136,321 kidney transplant recipients included in this study, 23,614 (17%) experienced death-censored graft loss over a median follow-up of 4.3 years (interquartile range, 1.9-7.8 years). The three-way donor-recipient body surface area ratio by donor age by recipient age interaction was statistically significant (P=0.04). The magnitude of the association between severe size mismatch (donor-recipient body surface area ratio <0.80 versus ≥1.00) and death-censored graft survival was stronger with older donor age and recipient age. In all recipient age categories except the youngest (18-30 years), 5- and 10-year graft survival rates were similar or better with a size-mismatched donor aged <40 years than a nonsize-mismatched donor aged 40 years or older.ConclusionsThe association of donor-recipient size mismatch on long-term graft survival is modulated by recipient and donor age. Size-mismatched kidneys yield excellent graft survival when the donor is young. Donor age was more strongly associated with graft survival than size mismatch.