RT Journal Article
SR Electronic
T1 Bone marrow age dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.18.476756
DO 10.1101/2022.01.18.476756
A1 Inamul Kabir
A1 Xinbo Zhang
A1 Jui Dave
A1 Raja Chakraborty
A1 Rihao Qu
A1 Rachana R. Chandran
A1 Aglaia Ntokou
A1 Binod Aryal
A1 Noemi Rotllan
A1 Rolando Garcia-Milian
A1 John Hwa
A1 Yuval Kluger
A1 Kathleen A. Martin
A1 Carlos Fernández-Hernando
A1 Daniel M. Greif
YR 2022
UL http://biorxiv.org/content/early/2022/01/21/2022.01.18.476756.abstract
AB Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cells (SMCs) clonally expand giving rise to up to ∼70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aging induces SMC polyclonality and worsens atherosclerosis through non-cell autonomous effects of aged bone marrow-derived cells. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin β3 resulting in increased cytokine (e.g., tumor necrosis factor [TNF]-α) signaling. In turn, TNFα induces recruitment and expansion of multiple SMCs into the atherosclerotic plaque. Recent studies demonstrate that normal aging is characterized by somatic mutations and clonal expansion of epithelial cells of diverse tissues (e.g., esophagus, endometrium, skin); extrapolating beyond atherogenesis, our results call for future studies evaluating the role of aged myeloid cells in regulating this epithelial cell clonal expansion.Competing Interest StatementThe authors have declared no competing interest.