Decoy TRAIL receptor CD264: a cell surface marker of cellular aging for human bone marrow-derived mesenchymal stem cells

Abstract

BackgroundMesenchymal stem cells (MSCs) are a mixture of progenitors that are heterogeneous in their regenerative potential. Development of MSC therapies with consistent efficacy is hindered by the absence of an immunophenotype of MSC heterogeneity. This study evaluates decoy TRAIL receptor CD264 as potentially the first surface marker to detect cellular aging in heterogeneous MSC cultures.MethodsCD264 surface expression, regenerative potential, and metrics of cellular aging were assessed in vitro for marrow MSCs from 12 donors ages 20–60 years old. Male and female donors were age matched.Expression of CD264 was compared with that of p16, p21, and p53 during serial passage of MSCs.ResultsWhen CD264+ cell content was 20% to 35%, MSC cultures from young (ages 20–40 years) and older (ages 45–60 years) donors proliferated rapidly and differentiated extensively. Older donor MSCs containing < 35% CD264+ cells had a small size and negligible senescence despite the donor’s advanced chronological age. Above the 35% threshold, CD264 expression inversely correlated with proliferation and differentiation potential. When CD264+ cell content was 75%, MSCs were enlarged and mostly senescent with severely compromised regenerative potential. There was no correlation of the older donors’ chronological age to either CD264+ cell content or the regenerative potential of the donor MSCs. CD264 was upregulated after p53 and had a similar expression profile to that of p21 during serial passage of MSCs. No sex-linked differences were detected in this study.ConclusionsThese results suggest that CD264 is a surface marker of cellular age for MSCs, not the chronological age of the MSC donor. CD264 is first upregulated in MSCs at an intermediate stage of cellular aging and remains upregulated as aging progresses towards senescence. The strong inverse correlation of CD264+ cell content to the regenerative potential of MSCs has possible application to assess the therapeutic potential of patient MSCs, standardize the composition and efficacy of MSC therapies, and facilitate aging research on MSCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0649-4) contains supplementary material, which is available to authorized users.

Survival of aging CD264+ and CD264− populations of human bone marrow mesenchymal stem cells is independent of colony‐forming efficiency

“…Increased levels of senescence in the CD264 + hBM‐MSCs compared with the CD264 − cells is consistent with a phenotype of cellular aging (Wagner et al, ). These findings agree with our prior observations that CD264 is first upregulated in hBM‐MSCs at an intermediate stage of cellular aging, which is characterized by diminished proliferation potential, and remains upregulated as aging progresses into senescence (Madsen et al, ).…”

“…Cellular aging of hBM‐MSCs was detected by expression of CD264, as we previously reported (Madsen et al, ). Heterogeneous cultures of transduced hBM‐MSCs were ~35% positive for CD264 expression based on a 1% isotype cutoff (Figure a,b), consistent with the content of CD264 + cells that we have observed for robust hBM‐MSC cultures (Madsen et al, ). P5 hBM‐MSCs were sorted into aging CD264 + and control CD264 − populations immediately before implantation to avoid artifacts in survival from differences in expansion and sorting conditions.…”

“…The in vivo persistence of aging CD264 + hBM‐MSCs reported here has ramifications for the preparation of hBM‐MSC therapies. Previous work in our lab has shown that CD264 + cells are present in hBM‐MSC cultures from young and older donors to different degrees (Madsen et al, ). Our current results indicate that aging CD264 + hBM‐MSCs will have comparable survival to healthy CD264 − cells.…”

“…This is consistent with previous reports of CD264 expression for hBM‐MSCs (Secchiero et al, ; Yulyana et al, ). In addition, we showed a strong inverse correlation of CD264 + cell content in hBM‐MSC cultures with their in vitro proliferation and differentiation potential (Madsen et al, ). The correlation agrees with the link between cellular aging and loss of stem cell fitness observed by others (Bertolo, Baur, Guerrero, Pötzel, & Stoyanov, ; Yang, Ogando, Wang See, Chang, & Barabino, ).…”

“…Our research group recently identified the decoy TRAIL receptor CD264 as the first known surface marker of cellular aging for hBM‐MSCs. CD264 is upregulated concomitantly with p21 at an intermediate stage of cellular aging and remains upregulated through senescence (Madsen et al, ). We detected CD264 + cells in all hBM‐MSC cultures in our study: CD264 + cell content ranged from 20% to 35% in hBM‐MSC cultures from young donors (ages 20–40 years old) and 20–75% in cultures from older donors (ages 45–60 years old; Madsen et al, ).…”