Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases.

TitleDiscovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases.
Publication TypeJournal Article
Year of Publication2023
AuthorsSun J, Hu L, Bok S, Yallowitz AR, Cung M, McCormick J, Zheng LJ, Debnath S, Niu Y, Tan AY, Lalani S, Morse KW, Shinn D, Pajak A, Li Z, Li N, Xu R, Iyer S, Greenblatt MB
JournalRes Sq
Date Published2023 Jan 25
Abstract

Vertebral bone is subject to a distinct set of disease processes from those of long bones, notably including a much higher rate of solid tumor metastases that cannot be explained by passive blood flow distribution alone. The basis for this distinct biology of vertebral bone has remained elusive. Here we identify a vertebral skeletal stem cell (vSSC), co-expressing the transcription factors ZIC1 and PAX1 together with additional cell surface markers, whose expression profile and function are markedly distinct from those of long bone skeletal stem cells (lbSSCs). vSSCs display formal evidence of stemness, including self-renewal, label retention and sitting at the apex of their differentiation hierarchy. Lineage tracing of vSSCs confirms that they make a persistent contribution to multiple mature cell lineages in the native vertebrae. vSSCs are physiologic mediators of spine mineralization, as genetic blockade of the ability of vSSCs to generate osteoblasts results in defects in the vertebral neural arch and body. Human counterparts of vSSCs can be identified in vertebral endplate specimens and display a conserved differentiation hierarchy and stemness. Multiple lines of evidence indicate that vSSCs contribute to the high rates of vertebral metastatic tropism observed clinically in breast cancer. Specifically, when an organoid system is used to place both vSSCs and lbSSCs in an identical anatomic context, vSSC-lineage cells are more efficient than lbSSC-lineage cells at recruiting metastases, a phenotype that is due in part to increased secretion of the novel metastatic trophic factor MFGE8. Similarly, genetically targeting loss-of-function to the vSSC lineage results in reduced metastasis rates in the native vertebral environment. Taken together, vSSCs are distinct from other skeletal stem cells and mediate the unique physiology and pathology of vertebrae, including contributing to the high rate of metastatic seeding of the vertebrae.

DOI10.21203/rs.3.rs-2106142/v1
Alternate JournalRes Sq
PubMed ID36747772
PubMed Central IDPMC9901027
Grant ListDP5 OD021351 / OD / NIH HHS / United States
K99 DE031819 / DE / NIDCR NIH HHS / United States
R01 AR075585 / AR / NIAMS NIH HHS / United States
Related Faculty: 
Matthew B. Greenblatt, M.D., Ph.D.

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