Bone Marrow-Derived CD44+ Cells Migrate to Tissue-Engineered Constructs via SDF-1/CXCR4-JNK Pathway and Aid Bone Repair.

Yanzhu Lu,Aijun Yang,Junchao Xing,Jianzhong Xu,Shiwu Dong,Jiyue Luo,Xiaolong Yin,Tianyong Hou,Xiaobo Zhu,Jing Gou

doi:10.1155/2019/1513526

Yanzhu Lu, Aijun Yang + Show 8 more

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https://doi.org/10.1155/2019/1513526

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Abstract

Background and Aims Host-derived cells play crucial roles in the regeneration process of tissue-engineered constructs (TECs) during the treatment of large segmental bone defects (LSBDs). However, their identity, source, and cell recruitment mechanisms remain elusive. Methods A complex model was created using mice by combining methods of GFP+ bone marrow transplantation (GFP-BMT), parabiosis (GFP+-BMT and wild-type mice), and femoral LSBD, followed by implantation of TECs or DBM scaffolds. Postoperatively, the migration of host BM cells was detected by animal imaging and immunofluorescent staining. Bone repair was evaluated by micro-CT. Signaling pathway repressors including AMD3100 and SP600125 associated with the migration of BM CD44+ cells were further investigated. In vitro, transwell migration and western-blotting assays were performed to verify the related signaling pathway. In vivo, the importance of the SDF-1/CXCR4-JNK pathway was validated by ELISA, fluorescence-activated cell sorting (FACS), immunofluorescent staining, and RT-PCR. Results First, we found that host cells recruited to facilitate TEC-mediated bone repair were derived from bone marrow and most of them express CD44, indicating the significance of CD44 in the migration of bone marrow cells towards donor MSCs. Then, the predominant roles of SDF-1/CXCR4 and downstream JNK in the migration of BM CD44+ cells towards TECs were demonstrated. Conclusion Together, we demonstrated that during bone repair promoted by TECs, BM-derived CD44+ cells were essential and their migration towards TECs could be regulated by the SDF-1/CXCR4-JNK signaling pathway.

Highlights

Large segmental bone defects (LSBDs) resulting from severe trauma, tumor resection, and debridement after infection are common and challenging in clinical settings [1, 2]
The effectiveness of tissue-engineered constructs (TECs), which are constituted by incorporating viable osteogenic progenitors (most usually mesenchymal stem cells (MSCs)) into 3D biocompatible scaffolds and delivering them to large segmental bone defects (LSBDs), has been proved by mounting evidence, including clinical trials with high confidence levels [3, 4]
These findings lead to more attention to the paracrine actions of MSCs; that is, secreting a variety of chemokines to attract host cells associated with tissue regeneration [8, 24]

Summary

Introduction

Large segmental bone defects (LSBDs) resulting from severe trauma, tumor resection, and debridement after infection are common and challenging in clinical settings [1, 2]. Host-derived cells play crucial roles in the regeneration process of tissue-engineered constructs (TECs) during the treatment of large segmental bone defects (LSBDs). Their identity, source, and cell recruitment mechanisms remain elusive. We found that host cells recruited to facilitate TEC-mediated bone repair were derived from bone marrow and most of them express CD44, indicating the significance of CD44 in the migration of bone marrow cells towards donor MSCs. the predominant roles of SDF-1/CXCR4 and downstream JNK in the migration of BM CD44+ cells towards TECs were demonstrated. We demonstrated that during bone repair promoted by TECs, BM-derived CD44+ cells were essential and their migration towards TECs could be regulated by the SDF-1/CXCR4-JNK signaling pathway

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Discussion

Conclusion