Hypoxia response element-directed expression of bFGF in dental pulp stem cells improve the hypoxic environment by targeting pericytes in SCI rats

Sipin Zhu; Yibo Ying; Yan He; Xingxing Zhong; Jiahui Ye; Zhiyang Huang; Min Chen; Qiuji Wu; Yifan Zhang; Ziyue Xiang; Yurong Tu; Weiyang Ying; Jian Xiao; Xiaokun Li; Qingsong Ye; Zhouguang Wang

doi:10.1016/j.bioactmat.2021.01.024

Hypoxia response element-directed expression of bFGF in dental pulp stem cells improve the hypoxic environment by targeting pericytes in SCI rats

Bioact Mater. 2021 Jan 30;6(8):2452-2466. doi: 10.1016/j.bioactmat.2021.01.024. eCollection 2021 Aug.

Authors

Sipin Zhu¹, Yibo Ying¹, Yan He², Xingxing Zhong³, Jiahui Ye¹, Zhiyang Huang¹, Min Chen¹, Qiuji Wu¹, Yifan Zhang¹, Ziyue Xiang¹, Yurong Tu¹, Weiyang Ying⁴, Jian Xiao^{5

6}, Xiaokun Li^{5

6}, Qingsong Ye^{7

8

9}, Zhouguang Wang^{1

5}

Affiliations

¹ Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
² Laboratory of Regenerative Medicine, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, 430064, China.
³ The Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, China.
⁴ Department of Pain Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
⁵ Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁶ Research Units of Clinical Translation of Cell Growth Factors and Diseases Research, Chinese Academy of Medical Science, China.
⁷ School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325035, China.
⁸ Massachusetts General Hospital, Harvard University, Boston, 02114, USA.
⁹ Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan, 630060, China.

Abstract

Cell-based transplantation strategies possess great potential for spinal cord injury (SCI) repair. Basic fibroblast growth factor (bFGF) has been reported to have multiple neuro-promoting effects on developing and adult nervous system of mammals and considered a promising therapy for nerve injury following SCI. Human dental pulp stem cells (DPSCs) are abundant stem cells with low immune rejection, which can be considered for cell replacement therapy. The purpose of this study was to investigate the roles of DPSCs which express bFGF under the regulation of five hypoxia-responsive elements (5HRE) using an adeno-associated virus (AAV-5HRE-bFGF-DPSCs) in SCI repairing model. In this study, DPSCs were revealed to differentiate into CD13⁺ pericytes and up-regulate N-cadherin expression to promote the re-attachment of CD13⁺ pericytes to vascular endothelial cells. The re-attachment of CD13⁺ pericytes to vascular endothelial cells subsequently increased the flow rate of blood in microvessels via the contraction of protuberance. As a result, increased numbers of red blood cells carried more oxygen to the damaged area and the local hypoxia microenvironment in SCI was improved. Thus, this study represents a step forward towards the potential use of AAV-5HRE-bFGF-DPSCs in SCI treatment in clinic.

Keywords: Adeno-associated virus; Basic fibroblast growth factor; Dental pulp stem cell; Hypoxic microenvironment; Spinal cord injury; Vascular regulation.