骨髓微环境中的WNT信号通路促进造血干细胞再生修复的研究

Hematopoietic stem cells (HSCs) are preserved in bone marrow (BM) microenvironment termed niche, which is critical for HSC maintenance and post-injury regeneration. Understanding HSC niche will considerably benefit stem cell and regenerative medicine research. Our preliminary data showed that Wnt10b-Frizzled7 axil promotes HSC regeneration post chemotherapeutic stress. We will further investigate the downstream mechanisms of Wnt10b-Frizzled7 axil and its potential clinical application. 1) How Wnt10b-Frizzled7 promotes HSC regeneration. 2) Whether Wnt10b-Frizzled7 facilitates umbilical cord blood HSC ex vivo expansion and their engraftment during stem cell transplantation. 3) Identify the cellular source of Wnt10b in bone marrow niche and further investigate whether manipulating Wnt10b in bone marrow niche can promote HSC regeneration and engraftment. The in-depth study of this project will open a new avenue for HSC regeneration studies. Specially regulating HSC function by manipulating their bone marrow niche will share light on stem cell based clinical therapy.

干细胞微环境是维持干细胞自我更新、分化和增殖能力的重要因素。如何通过干预骨髓微环境信号实现对造血干细胞功能的调控，是干细胞和再生医学领域的重要研究方向。申请人预实验发现WNT10b-Frizzled7促进造血干细胞化疗损伤后再生修复，本课题将在此基础上，对其细胞、分子机制和潜在临床应用意义展开系统研究：（1）WNT10b-Frizzled7调控造血干细胞化疗损伤后再生修复的分子机制和下游信号通路；（2）WNT10b-Frizzled7是否参与了人体脐带血来源造血干细胞的体外扩增以及移植成功率的调控；（3）WNT10b在骨髓微环境内的细胞来源，及其调控造血干细胞再生修复和移植成功率的潜在临床价值。实施此项针对骨髓微环境中WNT10b-Frizzled7信号通路调控造血干细胞损伤后修复和移植成功率的系统研究，可望在造血干细胞骨髓微环境研究领域开拓新的学术生长点，并具有重要理论和临床意义。

本项目系统研究了骨髓微环境信号调控造血细胞静息期维持和损伤修复的分子机制，发现微环境信号Wnt10b通过作用于造血干细胞的Fzd7受体激活下游β-catenin信号通路调控造血干细胞在化疗损伤后的再生修复，并进一步发现Wnt10b- Fzd7-β-catenin信号会激活造血干细胞的DNA损伤修复基因网络，从而促进的造血干细胞的DNA修复抑制DNA损伤和细胞凋亡。本研究还进一步发现Wnt10b重组蛋白能够在体外高效扩增脐带血来源造血干细胞，具有重要临床应用前景。