Unveiling Two Distinct Osteolineage Cell Populations Linked to Age-related Osteoporosis in Adult Mice Through Integrative Single-cell Analyses

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2025 Mar 11

PMID 40067455

Authors

Bo Zhou

Hongwen Huang

Zhen Ding

Kaiwen Luo

Yangshan Chen

Yingying Han

Wei Pang

Wanze Tang

Litong Chen

Wenfei Jin

Guixing Ma

Huiling Cao

Affiliations

Soon will be listed here.

Abstract

The bone marrow microenvironment contains heterogeneous stromal cells, which are critical for bone remodeling and provide essential supportive roles for hematopoietic functions. Although the diversity of PDGFRαβ mesenchymal stromal/stem cells (MSCs) get consensus, the osteo-lineage cells (OLCs) that constitute the developmental trajectory of osteoblasts are largely remain unclear. Here, we construct a comprehensive atlas of stromal cell via performing integrative single cell analyses for 77 samples from 14 datasets. Besides previously defined Lepr BM-MSCs derived OLC1, we present a novel OLC2 with unique molecular signatures and differentiation pathway. Both OLC1 and OLC2 show significant polygenic association with bone mineral density (BMD), while extracellular matrix (ECM) proteins specifically expressed by OLC2 are particularly decreased in bone tissue of aged mice. Notably, OLC1 and OLC2 are consistently reduced in aged mice, which might be induced by the decreased expression of several lineage drivers. Collectively, our study presents a thorough prospect of OLCs in the bone marrow microenvironment and highlights their important roles in age-related osteoporosis.

References

Ono N, Ono W, Nagasawa T, Kronenberg H . A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol. 2014; 16(12):1157-67. PMC: 4250334. DOI: 10.1038/ncb3067. View

Castanza A, Recla J, Eby D, Thorvaldsdottir H, Bult C, Mesirov J . Extending support for mouse data in the Molecular Signatures Database (MSigDB). Nat Methods. 2023; 20(11):1619-1620. PMC: 11397807. DOI: 10.1038/s41592-023-02014-7. View

Singer F . Paget's disease of bone-genetic and environmental factors. Nat Rev Endocrinol. 2015; 11(11):662-71. DOI: 10.1038/nrendo.2015.138. View

Mizoguchi T, Ono N . The diverse origin of bone-forming osteoblasts. J Bone Miner Res. 2021; 36(8):1432-1447. PMC: 8338797. DOI: 10.1002/jbmr.4410. View

Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D . Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013; 502(7473):637-43. PMC: 3821873. DOI: 10.1038/nature12612. View

Kim S . Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS One. 2018; 13(7):e0200785. PMC: 6062019. DOI: 10.1371/journal.pone.0200785. View

Baryawno N, Przybylski D, Kowalczyk M, Kfoury Y, Severe N, Gustafsson K . A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell. 2019; 177(7):1915-1932.e16. PMC: 6570562. DOI: 10.1016/j.cell.2019.04.040. View

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O . Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1):1523. PMC: 6447622. DOI: 10.1038/s41467-019-09234-6. View

Ding L, Saunders T, Enikolopov G, Morrison S . Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012; 481(7382):457-62. PMC: 3270376. DOI: 10.1038/nature10783. View

10.

Watanabe-Takano H, Ochi H, Chiba A, Matsuo A, Kanai Y, Fukuhara S . Mechanical load regulates bone growth via periosteal Osteocrin. Cell Rep. 2021; 36(2):109380. DOI: 10.1016/j.celrep.2021.109380. View

11.

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

12.

Yang G, He Q, Guo X, Li R, Lin J, Lang Y . Identification of the metaphyseal skeletal stem cell building trabecular bone. Sci Adv. 2024; 10(8):eadl2238. PMC: 10889359. DOI: 10.1126/sciadv.adl2238. View

13.

Boyle W, Simonet W, Lacey D . Osteoclast differentiation and activation. Nature. 2003; 423(6937):337-42. DOI: 10.1038/nature01658. View

14.

Crockett J, Rogers M, Coxon F, Hocking L, Helfrich M . Bone remodelling at a glance. J Cell Sci. 2011; 124(Pt 7):991-8. DOI: 10.1242/jcs.063032. View

15.

Worthley D, Churchill M, Compton J, Tailor Y, Rao M, Si Y . Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell. 2015; 160(1-2):269-84. PMC: 4436082. DOI: 10.1016/j.cell.2014.11.042. View

16.

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

17.

Hou X, Chen Y, Zhou B, Tang W, Ding Z, Chen L . Talin-1 inhibits Smurf1-mediated Stat3 degradation to modulate β-cell proliferation and mass in mice. Cell Death Dis. 2023; 14(10):709. PMC: 10616178. DOI: 10.1038/s41419-023-06235-8. View

18.

Schaum N, Lehallier B, Hahn O, Palovics R, Hosseinzadeh S, Lee S . Ageing hallmarks exhibit organ-specific temporal signatures. Nature. 2020; 583(7817):596-602. PMC: 7757734. DOI: 10.1038/s41586-020-2499-y. View

19.

Bergen V, Lange M, Peidli S, Wolf F, Theis F . Generalizing RNA velocity to transient cell states through dynamical modeling. Nat Biotechnol. 2020; 38(12):1408-1414. DOI: 10.1038/s41587-020-0591-3. View

20.

Zhou B, Yue R, Murphy M, Peyer J, Morrison S . Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. 2014; 15(2):154-68. PMC: 4127103. DOI: 10.1016/j.stem.2014.06.008. View