Aged skeletal stem cells generate an inflammatory degenerative niche

Thomas H. Ambrosi, Owen Marecic, Adrian McArdle, Rahul Sinha, Gunsagar S. Gulati, Xinming Tong, Yuting Wang, Holly M. Steininger, Malachia Y. Hoover, Lauren S. Koepke, Matthew P. Murphy, Jan Sokol, Eun Young Seo, Ruth Tevlin, Michael Lopez, Rachel E. Brewer, Shamik Mascharak, Laura Lu, Oyinkansola Ajanaku, Stephanie D. Conley, Jun Seita, Maurizio Morri, Norma F. Neff, Debashis Sahoo, Fan Yang, Irving L. Weissman, Michael T. Longaker () and Charles K. F. Chan ()
Additional contact information
Thomas H. Ambrosi: Stanford University School of Medicine
Owen Marecic: Stanford University School of Medicine
Adrian McArdle: Stanford University School of Medicine
Rahul Sinha: Stanford University School of Medicine
Gunsagar S. Gulati: Stanford University School of Medicine
Xinming Tong: Stanford University
Yuting Wang: Stanford University School of Medicine
Holly M. Steininger: Stanford University School of Medicine
Malachia Y. Hoover: Stanford University School of Medicine
Lauren S. Koepke: Stanford University School of Medicine
Matthew P. Murphy: Stanford University School of Medicine
Jan Sokol: Stanford University School of Medicine
Eun Young Seo: Stanford University School of Medicine
Ruth Tevlin: Stanford University School of Medicine
Michael Lopez: Stanford University School of Medicine
Rachel E. Brewer: Stanford University School of Medicine
Shamik Mascharak: Stanford University School of Medicine
Laura Lu: Stanford University School of Medicine
Oyinkansola Ajanaku: Stanford University School of Medicine
Stephanie D. Conley: Stanford University School of Medicine
Jun Seita: Stanford University School of Medicine
Maurizio Morri: Chan Zuckerberg BioHub
Norma F. Neff: Chan Zuckerberg BioHub
Debashis Sahoo: University of California San Diego
Fan Yang: Stanford University
Irving L. Weissman: Stanford University School of Medicine
Michael T. Longaker: Stanford University School of Medicine
Charles K. F. Chan: Stanford University School of Medicine

Nature, 2021, vol. 597, issue 7875, 256-262

Abstract: Abstract Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts1. Here we show that intrinsic ageing of skeletal stem cells (SSCs)2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system.

Date: 2021
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DOI: 10.1038/s41586-021-03795-7

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