Overexpression of NT3P75-2 gene modified bone marrow mesenchymal stem cells supernatant promotes neurological function recovery in ICH rats

Dongdong Huang; Han Bao; Jian Wu; Qichuan Zhuge; Jianjing Yang; Sheng Ye

doi:10.1016/j.neulet.2023.137067

Overexpression of NT3^P75-2 gene modified bone marrow mesenchymal stem cells supernatant promotes neurological function recovery in ICH rats

Neurosci Lett. 2023 Feb 6:796:137067. doi: 10.1016/j.neulet.2023.137067. Epub 2023 Jan 11.

Authors

Dongdong Huang¹, Han Bao¹, Jian Wu¹, Qichuan Zhuge¹, Jianjing Yang², Sheng Ye³

Affiliations

¹ Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
² Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: yangjianjing@wmu.edu.cn.
³ Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: wenzhouyesheng@126.com.

PMID: 36641043
DOI: 10.1016/j.neulet.2023.137067

Abstract

Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease with high mortality and long-term disability rates. Stem cell transplantation and neurotrophic factor therapy have shown great potential in ICH. It has been established that mutated NT3 (NT3^{P75 - 2}) can enhance the positive biological functions of NT3 by decreasing its affinity to the P75-2 receptor. The present study aimed to explore whether NT3^P75-2 could further improve neurological recovery after ICH. First, we constructed three stable BMSC cell lines (GFP, GFP-NT3 overexpressed and GFP-NT3^{P75 - 2} overexpressed) by lentivirus infection. Next, rats were injected with fresh supernatants of these three cell lines on days 1 (24 h) and 3 (72 h) post-ICH induction. Behavioral evaluations were conducted to assess the neurological recovery of ICH rats. We further evaluated changes in microglia activation, neuron survival and proliferation of neural stem cells. Compared with the GFP group and the GFP-NT3 group, animals in the GFP-NT3^{P75 - 2} group exhibited better motor function improvements and milder neuroinflammation response. Meanwhile, overexpression of NT3^{P75 - 2} significantly decreased neuronal apoptosis and increased number of SOX2 - positive cells. Taken together, our study demonstrated that early administration of NT3^{P75 - 2} enriched BMMSC supernatants significantly enhanced neuro-functional recovery after ICH by regulating neuroinflammation response, neuronal survival and increasing neural stem cell number, providing a new therapeutic strategy and direction for early treatment of ICH.

Keywords: Bone marrow mesenchymal stem cells; Intracerebral hemorrhage; M1/M2 microglia; NT3(P75 - 2); Neurological function recovery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Cells
Cerebral Hemorrhage / metabolism
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stem Cells* / metabolism
Neural Stem Cells* / metabolism
Neuroinflammatory Diseases
Rats
Recovery of Function / physiology

Substances

membrane protein, 75kDa