人骨髓间充质干细胞分泌的 EGFL7 部分通过下调 Notch1-Hes1 信号通路促进成骨细胞分化,Stem Cell Reviews and Reports

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人骨髓间充质干细胞分泌的 EGFL7 部分通过下调 Notch1-Hes1 信号通路促进成骨细胞分化
Stem Cell Reviews and Reports ( IF 4.5 ) Pub Date : 2023-01-07 , DOI: 10.1007/s12015-022-10503-z
Weijun Zhang _{1,

2,

3,

4} , Jinwu Bai _{1,

2,

3,

4} , Lijun Li _{1,

2,

3,

4} , Ye Zhang _{1,

2,

3,

4} , Kai Hang _{1,

2,

3,

4} , Yibo Wang _{1,

2,

3,

4} , Zhongxiang Wang _{1,

2,

3,

4} , Chenyi Ye _{1,

2,

3,

4} , Deting Xue _{1,

2,

3,

4}

Affiliation

背景

表皮生长因子样结构域蛋白 7 (EGFL7) 是一种在骨微环境中差异表达的分泌蛋白；然而，EGFL7 对人骨髓间充质干细胞 (hBMSC) 成骨的影响在很大程度上是未知的。

方法

基于 Gene Expression Omnibus (GEO) 数据库分析骨折微环境中的 EGFL7 表达。通过小干扰 RNA (siRNA) 敲低 EGFL7 和重组人 EGFL7 (rhEGFL7) 蛋白的体外刺激被用于评估下游信号转导的改变以及 hBMSC 的成骨分化和增殖的变化。γ-分泌酶抑制剂用于进一步探索 Notch 信号的抑制是否挽救了 hBMSC 中 EGFL7 敲低的成骨抑制作用。建立股骨缺损模型以验证重组小鼠EGFL7对体内骨愈合的影响。

结果

在 hBMSC 成骨过程中 EGFL7 表达增加。EGFL7 的敲低会损害 hBMSC 成骨并激活 Notch1/NICD/Hes1 信号。rhEGFL7 促进 hBMSC 成骨并下调 Notch1 信号。Notch1 信号抑制挽救了 EGFL7 敲低的成骨细胞抑制作用。重组 EGFL7 导致股骨缺损小鼠的骨愈合增强。

结论

EGFL7 部分通过下调 Notch1 信号来促进 hBMSC 的成骨。

图形概要

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EGFL7 Secreted By Human Bone Mesenchymal Stem Cells Promotes Osteoblast Differentiation Partly Via Downregulation Of Notch1-Hes1 Signaling Pathway

Background

Epidermal growth factor-like domain protein 7 (EGFL7) is a secreted protein that is differentially expressed in the bone microenvironment; however, the effect of EGFL7 on the osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) is largely unknown.

Methods

EGFL7 expression in the fracture microenvironment was analyzed based on the Gene Expression Omnibus (GEO) database. Knockdown of EGFL7 by small interfering RNA (siRNA) and in vitro stimulation with recombinant human EGFL7 (rhEGFL7) protein were used to assess alterations in downstream signaling and changes in the osteogenic differentiation and proliferation of hBMSCs. A γ-secretase inhibitor was used to further explore whether inhibition of Notch signaling rescued the osteogenic-inhibitory effect of EGFL7 knockdown in hBMSCs. A femoral defect model was established to verify the effect of recombinant mouse EGFL7 on bone healing in vivo.

Results

EGFL7 expression increased during hBMSC osteogenesis. Knockdown of EGFL7 impaired hBMSC osteogenesis and activated Notch1/NICD/Hes1 signaling. rhEGFL7 promoted hBMSC osteogenesis and downregulated Notch1 signaling. The osteoblast-inhibitory effect of EGFL7 knockdown was rescued by Notch1 signaling inhibition. Recombinant EGFL7 led to enhanced bone healing in mice with femoral defects.