Open AccessGeriatric fragility fractures are associated with a human skeletal stem cell defect
Author(s) -
Ambrosi Thomas H.,
Goodnough L. Henry,
Steininger Holly M.,
Hoover Malachia Y.,
Kim Emiley,
Koepke Lauren S.,
Marecic Owen,
Zhao Liming,
Seita Jun,
Bishop Julius A.,
Gardner Michael J.,
Chan Charles K. F.
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13164
Subject(s) - biology , stem cell , progenitor cell , wnt signaling pathway , transcriptome , downregulation and upregulation , senescence , microbiology and biotechnology , cancer research , signal transduction , genetics , gene expression , gene
Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age‐related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites ( n = 61) of patients ranging from 13 to 94 years of age for functional and molecular studies. We observed that fracture‐activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence‐related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re‐activation by trans‐resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age‐related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans.