Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Abstract Background Recent studies demonstrated that autologous mitochondria derived from bone marrow mesenchymal stem cells (BMSCs) might be valuable in the treatment of spinal cord injury (SCI). However, the mechanisms of mitochondrial transfer from BMSCs to injured neurons are not fully understood. Methods We modified BMSCs by CD157, a cell surface molecule as a potential regulator mitochondria transfer, then transplanted to SCI rats and co-cultured with OGD injured VSC4.1 motor neuron. We detected extracellular mitochondrial particles derived from BMSCs by transmission electron microscope and measured the CD157/cyclic ADP-ribose signaling pathway-related protein expression by immunohistochemistry and Western blotting assay. The CD157 ADPR-cyclase activity and Fluo-4 AM was used to detect the Ca2+ signal. All data were expressed as mean ± SEM. Statistical analysis was analyzed by GraphPad Prism 6 software. Unpaired t-test was used for the analysis of two groups. Multiple comparisons were evaluated by one-way ANOVA or two-way ANOVA. Results CD157 on BMSCs was upregulated when co-cultured with injured VSC4.1 motor neurons. Upregulation of CD157 on BMSCs could raise the transfer extracellular mitochondria particles to VSC4.1 motor neurons, gradually regenerate the axon of VSC4.1 motor neuron and reduce the cell apoptosis. Transplantation of CD157-modified BMSCs at the injured sites could significantly improve the functional recovery, axon regeneration, and neuron apoptosis in SCI rats. The level of Ca2+ in CD157-modified BMSCs dramatically increased when objected to high concentration cADPR, ATP content, and MMP of BMSCs also increased. Conclusion The present results suggested that CD157 can regulate the production and transfer of BMSC-derived extracellular mitochondrial particles, enriching the mechanism of the extracellular mitochondrial transfer in BMSCs transplantation and providing a novel strategy to improve the stem cell treatment on SCI.

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BDNF-Hypersecreting Human Mesenchymal Stem Cells Promote Functional Recovery, Axonal Sprouting, and Protection of Corticospinal Neurons after Spinal Cord Injury

Journal of Neuroscience ◽

10.1523/jneurosci.2769-09.2009 ◽

2009 ◽

Vol 29 (47) ◽

pp. 14932-14941 ◽

Cited By ~ 186

Author(s):

M. Sasaki ◽

C. Radtke ◽

A. M. Tan ◽

P. Zhao ◽

H. Hamada ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Functional Recovery ◽

Human Mesenchymal Stem Cells ◽

Axonal Sprouting ◽

Cord Injury

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Transplantation of Mesenchymal Stem Cells Promotes an Alternative Pathway of Macrophage Activation and Functional Recovery after Spinal Cord Injury

Journal of Neurotrauma ◽

10.1089/neu.2011.2109 ◽

2012 ◽

Vol 29 (8) ◽

pp. 1614-1625 ◽

Cited By ~ 220

Author(s):

Hideaki Nakajima ◽

Kenzo Uchida ◽

Alexander Rodriguez Guerrero ◽

Shuji Watanabe ◽

Daisuke Sugita ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Functional Recovery ◽

Macrophage Activation ◽

Alternative Pathway ◽

Cord Injury

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Repeated injections of human umbilical cord blood-derived mesenchymal stem cells significantly promotes functional recovery in rabbits with spinal cord injury of two noncontinuous segments

Stem Cell Research & Therapy ◽

10.1186/s13287-018-0879-0 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 15

Author(s):

Chaohua Yang ◽

Gaoju Wang ◽

Fenfen Ma ◽

Baoqing Yu ◽

Fancheng Chen ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Cord Blood ◽

Functional Recovery ◽

Umbilical Cord Blood ◽

Human Umbilical Cord Blood ◽

Human Umbilical Cord ◽

Cord Injury

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Intravenous infusion of mesenchymal stem cells promotes functional recovery in a model of chronic spinal cord injury

Neuroscience ◽

10.1016/j.neuroscience.2016.08.037 ◽

2016 ◽

Vol 335 ◽

pp. 221-231 ◽

Cited By ~ 55

Author(s):

Tomonori Morita ◽

Masanori Sasaki ◽

Yuko Kataoka-Sasaki ◽

Masahito Nakazaki ◽

Hiroshi Nagahama ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Functional Recovery ◽

Intravenous Infusion ◽

Chronic Spinal Cord Injury ◽

Cord Injury

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Human Brain–Derived Neurotrophic Factor Gene-Modified Bone Marrow Mesenchymal Stem Cells Combined With Erythropoietin Can Improve Acute Spinal Cord Injury

Dose-Response ◽

10.1177/1559325820910930 ◽

2020 ◽

Vol 18 (1) ◽

pp. 155932582091093

Author(s):

YongLei Li ◽

Hongchen Wang ◽

Xiaofang Ding ◽

Jiancheng Shen ◽

Haitao Zhou ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Bdnf Gene ◽

Factor Gene ◽

Cord Injury ◽

Marrow Mesenchymal Stem Cells

Objective: To assess the effect as well as mechanism of bone marrow mesenchymal stem cells (BMSCs) modified by the human brain–derived neurotrophic factor gene combined with erythropoietin (EPO) in the treatment of acute spinal cord injury (SCI) in rats. Methods: The Brain-derived neurotrophic factor (BDNF) gene was transected by a virus vector. Rats with SCI were randomly split into following groups: The normal saline (NS) group, the EPO group, The Basso, Beattie, and Bresnahan scores, messenger RNA BDNF expression, and apoptosis rates were compared between the 4 groups at 1, 3, 7, 14, and 21 days after SCI. Results: At 7, 14, and 21 days after operation, the expression of the BDNF gene in the other 3 groups was higher than that of the NS group, and the difference was statistically significant ( P < .05). The apoptosis rate in the combined group was less than that of NS, EPO, and BDNF/BMSC groups, and the differences were statistically significant ( P < .05). Conclusion: Brain-derived neurotrophic factor gene-modified BMSC transplantation combined with EPO can promote the repair of nerve function after SCI in rats.

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