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IGF-1 overexpression improves mesenchymal stem cell survival and promotes neurological recovery after spinal cord injury.

ABSTRACT: BACKGROUND:Survival and therapeutic actions of bone marrow-derived mesenchymal stem cells (BMMSCs) can be limited by the hostile microenvironment present during acute spinal cord injury (SCI). Here, we investigated whether BMMSCs overexpressing insulin-like growth factor 1 (IGF-1), a cytokine involved in neural development and injury repair, improved the therapeutic effects of BMMSCs in SCI. METHODS:Using a SCI contusion model in C57Bl/6 mice, we transplanted IGF-1 overexpressing or wild-type BMMSCs into the lesion site following SCI and evaluated cell survival, proliferation, immunomodulation, oxidative stress, myelination, and functional outcomes. RESULTS:BMMSC-IGF1 transplantation was associated with increased cell survival and recruitment of endogenous neural progenitor cells compared to BMMSC- or saline-treated controls. Modulation of gene expression of pro- and anti-inflammatory mediators was observed after BMMSC-IGF1 and compared to saline- and BMMSC-treated mice. Treatment with BMMSC-IGF1 restored spinal cord redox homeostasis by upregulating antioxidant defense genes. BMMSC-IGF1 protected against SCI-induced myelin loss, showing more compact myelin 28?days after SCI. Functional analyses demonstrated significant gains in BMS score and gait analysis in BMMSC-IGF1, compared to BMMSC or saline treatment. CONCLUSIONS:Overexpression of IGF-1 in BMMSC resulted in increased cell survival, immunomodulation, myelination, and functional improvements, suggesting that IGF-1 facilitates the regenerative actions of BMMSC in acute SCI.

SUBMITTER: Allahdadi KJ

PROVIDER: S-EPMC6530133 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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IGF-1 overexpression improves mesenchymal stem cell survival and promotes neurological recovery after spinal cord injury.

Allahdadi Kyan James KJ de Santana Thaís Alves TA Santos Girlaine Café GC Azevedo Carine Machado CM Mota Roberta Alves RA Nonaka Carolina Kymie CK Silva Daniela Nascimento DN Valim Clarissa Xavier Resende CXR Figueira Cláudio Pereira CP Dos Santos Washington Luis Conrado WLC do Espirito Santo Renan Fernandes RF Evangelista Afrânio Ferreira AF Villarreal Cristiane Flora CF Dos Santos Ricardo Ribeiro RR de Souza Bruno Solano Freitas BSF Soares Milena Botelho Pereira MBP

Stem cell research & therapy 20190521 1

<h4>Background</h4>Survival and therapeutic actions of bone marrow-derived mesenchymal stem cells (BMMSCs) can be limited by the hostile microenvironment present during acute spinal cord injury (SCI). Here, we investigated whether BMMSCs overexpressing insulin-like growth factor 1 (IGF-1), a cytokine involved in neural development and injury repair, improved the therapeutic effects of BMMSCs in SCI.<h4>Methods</h4>Using a SCI contusion model in C57Bl/6 mice, we transplanted IGF-1 overexpressing ...[more]

PMID: 31113444

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Project description:Chronic compressive spinal cord injury in compressive cervical myelopathy conditions can lead to rapid neurological deterioration in the early phase, followed by partial self-recovery, and ultimately an equilibrium state of neurological dysfunction. Ferroptosis is a crucial pathological process in many neurodegenerative diseases; however, its role in chronic compressive spinal cord injury remains unclear. In this study, we established a chronic compressive spinal cord injury rat model, which displayed its most severe behavioral and electrophysiological dysfunction at 4 weeks and partial recovery at 8 weeks after compression. Bulk RNA sequencing data identified enriched functional pathways, including ferroptosis, presynapse, and postsynaptic membrane activity at both 4 and 8 weeks following chronic compressive spinal cord injury. Transmission electron microscopy and malondialdehyde quantification assay confirmed that ferroptosis activity peaked at 4 weeks and was attenuated at 8 weeks after chronic compression. Ferroptosis activity was negatively correlated with behavioral score. Immunofluorescence, quantitative polymerase chain reaction, and western blotting showed that expression of the anti-ferroptosis molecules, glutathione peroxidase 4 (GPX4) and MAF BZIP transcription factor G (MafG), in neurons was suppressed at 4 weeks and upregulated at 8 weeks following spinal cord compression. There was a positive correlation between the expression of these two molecules, suggesting that they may work together to contribute to functional recovery following chronic compressive spinal cord injury. In conclusion, our study determined the genome-wide expression profile and ferroptosis activity of a consistently compressed spinal cord at different time points. The results showed that anti-ferroptosis genes, specifically GPX4 and MafG, may be involved in spontaneous neurological recovery at 8 weeks of chronic compressive spinal cord injury. These findings contribute to a better understanding of the mechanisms underlying chronic compressive spinal cord injury and may help identify new therapeutic targets for compressive cervical myelopathy.

Dataset Information

IGF-1 overexpression improves mesenchymal stem cell survival and promotes neurological recovery after spinal cord injury.

Publications

IGF-1 overexpression improves mesenchymal stem cell survival and promotes neurological recovery after spinal cord injury.

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