Aged skeletal stem cells generate an inflammatory degenerative niche.

Autor:	Ambrosi TH; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Marecic O; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., McArdle A; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Sinha R; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA., Gulati GS; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA., Tong X; Department of Bioengineering, Stanford University, Stanford, CA, USA., Wang Y; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Steininger HM; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Hoover MY; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Koepke LS; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Murphy MP; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Sokol J; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Seo EY; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Tevlin R; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Lopez M; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Brewer RE; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA., Mascharak S; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.; Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA., Lu L; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.; Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA., Ajanaku O; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.; Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA., Conley SD; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA., Seita J; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Center for Integrative Medical Sciences and Advanced Data Science Project, RIKEN, Tokyo, Japan., Morri M; Chan Zuckerberg BioHub, San Francisco, CA, USA., Neff NF; Chan Zuckerberg BioHub, San Francisco, CA, USA., Sahoo D; Pediatrics, and Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA., Yang F; Department of Bioengineering, Stanford University, Stanford, CA, USA., Weissman IL; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Ludwig Center for Cancer Stem Cell Biology and Medicine at Stanford University, Stanford, CA, USA., Longaker MT; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. longaker@stanford.edu.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. longaker@stanford.edu.; Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA. longaker@stanford.edu., Chan CKF; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. chazchan@stanford.edu.; Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA. chazchan@stanford.edu.; Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA. chazchan@stanford.edu.
Jazyk:	angličtina
Zdroj:	Nature [Nature] 2021 Sep; Vol. 597 (7875), pp. 256-262. Date of Electronic Publication: 2021 Aug 11.
DOI:	10.1038/s41586-021-03795-7
Abstrakt:	Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts 1 . 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. (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze:	MEDLINE
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