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.

在先前对人骨髓基质细胞（BMSCs，也称为骨髓来源的“间充质干细胞”）的转录组学研究中，SFRP2在多能 BMSCs（骨骼干细胞，SSCs）的一个子集中高度过量表达，这些细胞重新创建体内异位骨形成试验中的骨/骨髓器官。SFRPs 调节 WNT 信号，这对维持骨骼稳态至关重要，但 SFRP2 在 BMSCs/SSCs 中的具体作用尚不清楚。在这里，我们评估了骨骼器官发生和再生模型中 BMSC/SSC 功能的Sfrp2缺陷。Sfrp2缺陷 (KO) 小鼠的骨骼明显正常；但他们的 BMSCs/SSCs 表现出较低的集落形成效率，反映出较低的 SSC 自我更新/丰度。sfrp2在异位骨形成测定中，KO BMSCs/SSCs 形成的骨小梁少于来自WT同窝仔的骨小梁。此外，皮质钻孔缺陷的再生在Sfrp2 KO 小鼠中显着受损。Sfrp2缺陷型 BMSCs/SSCs 表现出较差的体外成骨分化，如通过Runx2和Osterix表达和钙积累所测量的。有趣的是，Wnt 共受体 Lrp6 的激活和 Wnt 靶基因Axin2、C-myc和细胞周期蛋白 D1的表达在Sfrp2中降低-有缺陷的 BMSC/SSC。添加重组 Sfrp2 恢复了大部分这些活动，表明 Sfrp2 充当 Wnt 激动剂。我们证明Sfrp2在 SSC 的自我更新以及骨愈合期间成人 SSC 的募集和分化中发挥作用。SFRP2 也是 BMSC/SSC 多能性的有用标记，也是潜在提高离体扩增 BMSC/SSC 产品质量的一个因素。