Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice

Abstract In a previous transcriptomic study of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived “mesenchymal stem cells”), SFRP2 was highly over-represented in a subset of multipotent BMSCs (skeletal stem cells, SSCs), which recreate a bone/marrow organ in an in vivo ectopic...

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Autores principales:	Luis Fernandez de Castro, Brian J. Sworder, Byron Mui, Kathryn Futrega, Agnes Berendsen, Matthew D. Phillips, Nathan J. Burbach, Natasha Cherman, Sergei Kuznetsov, Yankel Gabet, Kenn Holmbeck, Pamela G. Robey
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Biology (General) QH301-705.5 Physiology QP1-981
Acceso en línea:	https://doaj.org/article/01a82cd57e0d47c091b9d82673e78dcd
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spelling	oai:doaj.org-article:01a82cd57e0d47c091b9d82673e78dcd2021-12-05T12:06:16ZSecreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice10.1038/s41413-021-00169-72095-6231https://doaj.org/article/01a82cd57e0d47c091b9d82673e78dcd2021-12-01T00:00:00Zhttps://doi.org/10.1038/s41413-021-00169-7https://doaj.org/toc/2095-6231Abstract In a previous transcriptomic study of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived “mesenchymal stem cells”), SFRP2 was highly over-represented in a subset of multipotent BMSCs (skeletal stem cells, SSCs), which recreate a bone/marrow organ in an in vivo ectopic bone formation assay. SFRPs modulate WNT signaling, which is essential to maintain skeletal homeostasis, but the specific role of SFRP2 in BMSCs/SSCs is unclear. Here, we evaluated Sfrp2 deficiency on BMSC/SSC function in models of skeletal organogenesis and regeneration. The skeleton of Sfrp2-deficient (KO) mice is overtly normal; but their BMSCs/SSCs exhibit reduced colony-forming efficiency, reflecting low SSC self-renewal/abundancy. Sfrp2 KO BMSCs/SSCs formed less trabecular bone than those from WT littermates in the ectopic bone formation assay. Moreover, regeneration of a cortical drilled hole defect was dramatically impaired in Sfrp2 KO mice. Sfrp2-deficient BMSCs/SSCs exhibited poor in vitro osteogenic differentiation as measured by Runx2 and Osterix expression and calcium accumulation. Interestingly, activation of the Wnt co-receptor, Lrp6, and expression of Wnt target genes, Axin2, C-myc and Cyclin D1, were reduced in Sfrp2-deficient BMSCs/SSCs. Addition of recombinant Sfrp2 restored most of these activities, suggesting that Sfrp2 acts as a Wnt agonist. We demonstrate that Sfrp2 plays a role in self-renewal of SSCs and in the recruitment and differentiation of adult SSCs during bone healing. SFRP2 is also a useful marker of BMSC/SSC multipotency, and a factor to potentially improve the quality of ex vivo expanded BMSC/SSC products.Luis Fernandez de CastroBrian J. SworderByron MuiKathryn FutregaAgnes BerendsenMatthew D. PhillipsNathan J. BurbachNatasha ChermanSergei KuznetsovYankel GabetKenn HolmbeckPamela G. RobeyNature Publishing GrouparticleBiology (General)QH301-705.5PhysiologyQP1-981ENBone Research, Vol 9, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5 Physiology QP1-981
spellingShingle	Biology (General) QH301-705.5 Physiology QP1-981 Luis Fernandez de Castro Brian J. Sworder Byron Mui Kathryn Futrega Agnes Berendsen Matthew D. Phillips Nathan J. Burbach Natasha Cherman Sergei Kuznetsov Yankel Gabet Kenn Holmbeck Pamela G. Robey Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice
description	Abstract In a previous transcriptomic study of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived “mesenchymal stem cells”), SFRP2 was highly over-represented in a subset of multipotent BMSCs (skeletal stem cells, SSCs), which recreate a bone/marrow organ in an in vivo ectopic bone formation assay. SFRPs modulate WNT signaling, which is essential to maintain skeletal homeostasis, but the specific role of SFRP2 in BMSCs/SSCs is unclear. Here, we evaluated Sfrp2 deficiency on BMSC/SSC function in models of skeletal organogenesis and regeneration. The skeleton of Sfrp2-deficient (KO) mice is overtly normal; but their BMSCs/SSCs exhibit reduced colony-forming efficiency, reflecting low SSC self-renewal/abundancy. Sfrp2 KO BMSCs/SSCs formed less trabecular bone than those from WT littermates in the ectopic bone formation assay. Moreover, regeneration of a cortical drilled hole defect was dramatically impaired in Sfrp2 KO mice. Sfrp2-deficient BMSCs/SSCs exhibited poor in vitro osteogenic differentiation as measured by Runx2 and Osterix expression and calcium accumulation. Interestingly, activation of the Wnt co-receptor, Lrp6, and expression of Wnt target genes, Axin2, C-myc and Cyclin D1, were reduced in Sfrp2-deficient BMSCs/SSCs. Addition of recombinant Sfrp2 restored most of these activities, suggesting that Sfrp2 acts as a Wnt agonist. We demonstrate that Sfrp2 plays a role in self-renewal of SSCs and in the recruitment and differentiation of adult SSCs during bone healing. SFRP2 is also a useful marker of BMSC/SSC multipotency, and a factor to potentially improve the quality of ex vivo expanded BMSC/SSC products.
format	article
author	Luis Fernandez de Castro Brian J. Sworder Byron Mui Kathryn Futrega Agnes Berendsen Matthew D. Phillips Nathan J. Burbach Natasha Cherman Sergei Kuznetsov Yankel Gabet Kenn Holmbeck Pamela G. Robey
author_facet	Luis Fernandez de Castro Brian J. Sworder Byron Mui Kathryn Futrega Agnes Berendsen Matthew D. Phillips Nathan J. Burbach Natasha Cherman Sergei Kuznetsov Yankel Gabet Kenn Holmbeck Pamela G. Robey
author_sort	Luis Fernandez de Castro
title	Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice
title_short	Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice
title_full	Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice
title_fullStr	Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice
title_full_unstemmed	Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice
title_sort	secreted frizzled related-protein 2 (sfrp2) deficiency decreases adult skeletal stem cell function in mice
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/01a82cd57e0d47c091b9d82673e78dcd
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Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice

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