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.
Highlights
Bone marrow stromal cells (BMSCs, referred to as bone marrow-derived “mesenchymal stem cells”), are a population of non-hematopoietic, rapidly adherent fibroblastic cells first described by Friedenstein and Owen [reviewed in refs. 1,2] Nonclonal strains of BMSCs generate cartilage in an in vitro cell pellet assay, as well as osteogenic cells, hematopoiesis-supportive stroma and marrow adipocytes upon in vivo transplantation with appropriate scaffolds, based on the presence of a subset of skeletal stem cells (SSCs) within bone marrow stromal cells.[3]
The same marked by the expression of VE-Cad, Lepr and the Col 2.3 kb number of transplanted Sfrp[2] KO BMSCs failed to fully resorb the promoter (Col1a1) to identify vascular, bone marrow-derived gelatin scaffold material, and did not stem/progenitor cells, and osteoblasts at steady state, respectively (see[29] completely establish a normal ossicle. μCT analysis (Fig. 3d, e) showed less trabecular bone in Sfrp[2] KO transplants (Tb.BV/TV), for experimental details)
We found that Th, and Tb.Sp, respectively), that was structurally altered Sfrp2+ cells were localized within the Lepr+ population, (Fig. 3e)
Summary
Bone marrow stromal cells (BMSCs, referred to as bone marrow-derived “mesenchymal stem cells”), are a population of non-hematopoietic, rapidly adherent fibroblastic cells first described by Friedenstein and Owen [reviewed in refs. 1,2] Nonclonal strains of BMSCs generate cartilage in an in vitro cell pellet assay, as well as osteogenic cells, hematopoiesis-supportive stroma and marrow adipocytes upon in vivo transplantation with appropriate scaffolds, based on the presence of a subset of skeletal stem cells (SSCs) within bone marrow stromal cells (bmSSCs).[3]. Bone marrow stromal cells (BMSCs, referred to as bone marrow-derived “mesenchymal stem cells”), are a population of non-hematopoietic, rapidly adherent fibroblastic cells first described by Friedenstein and Owen [reviewed in refs. 1,2] Nonclonal strains of BMSCs generate cartilage in an in vitro cell pellet assay, as well as osteogenic cells, hematopoiesis-supportive stroma and marrow adipocytes upon in vivo transplantation with appropriate scaffolds, based on the presence of a subset of skeletal stem cells (SSCs) within bone marrow stromal cells (bmSSCs).[3] These cells are anatomically, phenotypically and functionally distinct from SSCs within the developing growth plate (gpSSCs), and in the periosteum (pSSCs)[4,5,6,7,8] The transcriptomic profile of aliquots of the M-SCDSs and F-SCDSs cultures used for in vivo transplantation were compared, and SFRP2 gene was highly and consistently over-represented in M-SCDSs, suggesting its potential role in SSCs.[11]
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