Abstract
BackgroundSurvival 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.MethodsUsing 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.ResultsBMMSC-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.ConclusionsOverexpression 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.
Highlights
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)
The number of Green fluorescent protein (GFP)+ cells detected in the SCI epicenter 5 days post-injury was higher in mice transplanted with BMMSC-IGF1 than with wild-type BMMSCs (Fig. 1a, b)
This was confirmed by GFP gene expression analysis by RT-qPCR, which demonstrated increased GFP gene expression in the spinal cord of mice transplanted with BMMSC-IGF1, when compared to those receiving wild-type BMMSCs (Fig. 1c)
Summary
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). 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. Stem cell therapy is a promising field that has been investigated as a therapeutic option for SCI [4]. BMMSCs can promote SCI recovery through the immunomodulation [5], activation, and homing of endogenous stem/progenitor cells [6] and by the production of growth factors, neuroprotective cytokines, and chemokines [7, 8]. Genetic engineering of BMMSCs is a promising approach to improve cell survival and influence surround tissue via paracrine actions, through overexpression of specific growth factors of interest [9]
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