Abstract
ObjectivesTo investigate the safety for clinic use and therapeutic effects of basic fibroblast growth factor (bFGF)-overexpressing human umbilical cord-derived mesenchymal stem cells (HUCMSCs) in mice with completely transected spinal cord injury (SCI).MethodsStable bFGF-overexpressing HUCMSCs clones were established by electrotransfection and then subjected to systematic safety evaluations. Then, bFGF-overexpressing and control HUCMSCs were used to treat mice with completely transected SCI by tail intravenous injection. Therapeutic outcomes were then investigated, including functional recovery of locomotion, histological structures, nerve regeneration, and recovery mechanisms.ResultsStable bFGF-overexpressing HUCMSCs met the standards and safety of MSCs for clinic use. In the mouse SCI model, stable bFGF-overexpressing HUCMSCs markedly improved therapeutic outcomes such as reducing glial scar formation, improving nerve regeneration and proliferation of endogenous neural stem cells (NSCs), and increasing locomotion functional recovery of posterior limbs compared with the control HUCMSCs group. Furthermore, bFGF-overexpressing HUCMSCs promoted the proliferation and neuronal differentiation of NSCs in vitro through the PI3K-Akt-GSK-3β pathway.ConclusionbFGF-overexpressing HUCMSCs meet the requirements of clinical MSCs and improve evident therapeutic outcomes of mouse SCI treatment, which firmly supports the safety and efficacy of gene-modified MSCs for clinical application.
Highlights
Spinal cord injury (SCI) is a severe, highly disabling, and fatal disease that is mostly caused by accidents [1]
Our results showed that basic fibroblast growth factor (bFGF)-overexpressing human umbilical cord-derived mesenchymal stem cells (HUCMSCs) met the standards and safety for clinic use of MSCs and markedly improved therapeutic outcomes such as reducing glial scar formation, improving nerve regeneration and proliferation of endogenous neural stem cells (NSCs), and increasing locomotion functional recovery compared with control HUCMSC treatment
We found that when co-cultured NSCs with interleukin- 2 (IL2)-bFGF-overexpressing HUCMSC and bFGF-overexpressing HUCMSC respectively, the proliferation and neuronal differentiation of NSCs were higher in IL2-bFGF-HUCMSCs than in bFGF-HUCMSCs, indicating IL2 recombinant bFGF still had the biological activity of bFGF, the better therapeutic effect of IL2-bFGF-HUCMSCs was dependent on higher secreted dose
Summary
Spinal cord injury (SCI) is a severe, highly disabling, and fatal disease that is mostly caused by accidents [1]. SCI leads to severance of axons and death of neurons, which result in permanent functional impairments [2]. In SCI, the initial mechanical action induces the primary injury that leads to secondary injury due to numerous factors such as inflammation, ischemia, lipid peroxidation, and apoptosis [2,3,4,5]. The exact pathophysiological mechanisms remain unknown, preclinical studies have made major progress in neuroprotection and regeneration such as promoting long-distance axonal growth. No major breakthroughs translatable to therapy have been achieved and many challenges remain for basic research and clinical treatment of SCI [6, 7]. In addition to traditional management of SCI, such as medical, surgical, and rehabilitative treatments, gene therapy and cell transplantation, which are the most promising treatment options, have been applied to SCI therapy in recent years [8, 9]
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