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Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases

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. Her...

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Autores principales: Sun, Jun, Hu, Lingling, Bok, Seoyeon, Yallowitz, Alisha R, Cung, Michelle, McCormick, Jason, Zheng, Ling J, Debnath, Shawon, Niu, Yuzhe, Tan, Adrian Y, Lalani, Sarfaraz, Morse, Kyle W, Shinn, Daniel, Pajak, Anthony, Li, Zan, Li, Na, Xu, Ren, Iyer, Sravisht, Greenblatt, Matthew B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901027/
https://www.ncbi.nlm.nih.gov/pubmed/36747772
http://dx.doi.org/10.21203/rs.3.rs-2106142/v1
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author Sun, Jun
Hu, Lingling
Bok, Seoyeon
Yallowitz, Alisha R
Cung, Michelle
McCormick, Jason
Zheng, Ling J
Debnath, Shawon
Niu, Yuzhe
Tan, Adrian Y
Lalani, Sarfaraz
Morse, Kyle W
Shinn, Daniel
Pajak, Anthony
Li, Zan
Li, Na
Xu, Ren
Iyer, Sravisht
Greenblatt, Matthew B
author_facet Sun, Jun
Hu, Lingling
Bok, Seoyeon
Yallowitz, Alisha R
Cung, Michelle
McCormick, Jason
Zheng, Ling J
Debnath, Shawon
Niu, Yuzhe
Tan, Adrian Y
Lalani, Sarfaraz
Morse, Kyle W
Shinn, Daniel
Pajak, Anthony
Li, Zan
Li, Na
Xu, Ren
Iyer, Sravisht
Greenblatt, Matthew B
author_sort Sun, Jun
collection PubMed
description 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.
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spelling pubmed-99010272023-02-07 Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases Sun, Jun Hu, Lingling Bok, Seoyeon Yallowitz, Alisha R Cung, Michelle McCormick, Jason Zheng, Ling J Debnath, Shawon Niu, Yuzhe Tan, Adrian Y Lalani, Sarfaraz Morse, Kyle W Shinn, Daniel Pajak, Anthony Li, Zan Li, Na Xu, Ren Iyer, Sravisht Greenblatt, Matthew B Res Sq Article 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. American Journal Experts 2023-01-25 /pmc/articles/PMC9901027/ /pubmed/36747772 http://dx.doi.org/10.21203/rs.3.rs-2106142/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Sun, Jun
Hu, Lingling
Bok, Seoyeon
Yallowitz, Alisha R
Cung, Michelle
McCormick, Jason
Zheng, Ling J
Debnath, Shawon
Niu, Yuzhe
Tan, Adrian Y
Lalani, Sarfaraz
Morse, Kyle W
Shinn, Daniel
Pajak, Anthony
Li, Zan
Li, Na
Xu, Ren
Iyer, Sravisht
Greenblatt, Matthew B
Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases
title Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases
title_full Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases
title_fullStr Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases
title_full_unstemmed Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases
title_short Discovery of a Vertebral Skeletal Stem Cell Driving Spinal Metastases
title_sort discovery of a vertebral skeletal stem cell driving spinal metastases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9901027/
https://www.ncbi.nlm.nih.gov/pubmed/36747772
http://dx.doi.org/10.21203/rs.3.rs-2106142/v1
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