Double gene therapy with granulocyte colony-stimulating factor and vascular endothelial growth factor acts synergistically to improve nerve regeneration and functional outcome after sciatic nerve injury in mice

Lopes, Francisco R.; Martin, Priscila Keiko Matsumoto; Frattini, Flávia; Biancalana, Adriano; Almeida, Fernanda Martins de; Tomaz, Marcelo Antônio; Melo, Paulo A.; Borojević, Radovan; Han, Seongho; Martínez, Ana Maria Blanco

doi:10.1016/j.neuroscience.2012.10.025

Cited by 35 publications

(18 citation statements)

References 108 publications

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“…That G-CSF alone was only able to produce short-lived improvements in motor function suggests that the present drug regimen (single injection of G-CSF) may need to be optimized, such as repeated treatments especially during the chronic stage to achieve long-lasting benefits. Indeed, studies have shown modest behavioral effects with G-CSF treatments in animal models of neurological disorders [63], [64], [65]. On the other hand, hUCB alone seemed to afford much more improved behavioral outcomes with robust and stable recovery of motor functions in chronic TBI animals, indicating that the stem/progenitor cells may be accomplishing a much more widespread biological action than the drug therapy.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

et al. 2014

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Traumatic brain injury (TBI) is associated with neuro-inflammation, debilitating sensory-motor deficits, and learning and memory impairments. Cell-based therapies are currently being investigated in treating neurotrauma due to their ability to secrete neurotrophic factors and anti-inflammatory cytokines that can regulate the hostile milieu associated with chronic neuroinflammation found in TBI. In tandem, the stimulation and mobilization of endogenous stem/progenitor cells from the bone marrow through granulocyte colony stimulating factor (G-CSF) poses as an attractive therapeutic intervention for chronic TBI. Here, we tested the potential of a combined therapy of human umbilical cord blood cells (hUCB) and G-CSF at the acute stage of TBI to counteract the progressive secondary effects of chronic TBI using the controlled cortical impact model. Four different groups of adult Sprague Dawley rats were treated with saline alone, G-CSF+saline, hUCB+saline or hUCB+G-CSF, 7-days post CCI moderate TBI. Eight weeks after TBI, brains were harvested to analyze hippocampal cell loss, neuroinflammatory response, and neurogenesis by using immunohistochemical techniques. Results revealed that the rats exposed to TBI treated with saline exhibited widespread neuroinflammation, impaired endogenous neurogenesis in DG and SVZ, and severe hippocampal cell loss. hUCB monotherapy suppressed neuroinflammation, nearly normalized the neurogenesis, and reduced hippocampal cell loss compared to saline alone. G-CSF monotherapy produced partial and short-lived benefits characterized by low levels of neuroinflammation in striatum, DG, SVZ, and corpus callosum and fornix, a modest neurogenesis, and a moderate reduction of hippocampal cells loss. On the other hand, combined therapy of hUCB+G-CSF displayed synergistic effects that robustly dampened neuroinflammation, while enhancing endogenous neurogenesis and reducing hippocampal cell loss. Vigorous and long-lasting recovery of motor function accompanied the combined therapy, which was either moderately or short-lived in the monotherapy conditions. These results suggest that combined treatment rather than monotherapy appears optimal for abrogating histophalogical and motor impairments in chronic TBI.

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Section: Discussionmentioning

confidence: 99%

Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

et al. 2014

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“…Restoration of function after nerve transection and injuries causing nerve defects requires surgical intervention[12]. If untreated, such injuries result in partial or total paralysis.…”

Section: Introductionmentioning

confidence: 99%

Sensory reinnervation of muscle spindles after repair of tibial nerve defects using autogenous vein grafts

2014

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Motor reinnervation after repair of tibial nerve defects using autologous vein grafts in rats has previously been reported, but sensory reinnervation after the same repair has not been fully investigated. In this study, partial sensory reinnervation of muscle spindles was observed after repair of 10-mm left tibial nerve defects using autologous vein grafts with end-to-end anastomosis in rats, and functional recovery was confirmed by electrophysiological studies. There were no significant differences in the number, size, or electrophysiological function of reinnervated muscle spindles between the two experimental groups. These findings suggest that repair of short nerve defects with autologous vein grafts provides comparable results to immediate end-to-end anastomosis in terms of sensory reinnervation of muscle spindles.

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“…Increasing experimental schemes focusing on either BMSCs implanting or G‐CSF intervention have been designed to advance peripheral nerve regeneration through acellular nerve grafts. However, the restoration of neural function is less than satisfactory compared with autografting (Pang et al, ; Pereira Lopes et al, ). Accordingly, in the present study the application of G‐CSF and BMSCs was conducted with heterogeneous acellular nerve grafting, and the effectiveness of the combined therapy was assessed.…”

Section: Discussionmentioning

confidence: 99%

Combination of BMSCs‐laden acellular nerve xenografts transplantation and G‐CSF administration promotes sciatic nerve regeneration

Hua

Wang²,

Chen

et al. 2019

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Peripheral nerve gaps often lead to interrupted innervation, manifesting as severe sensory and motor dysfunctions. The repairs of the nerve injuries have not achieved satisfactory curative effects in clinic. The transplantation of bone marrow stromal cells (BMSCs)-laden acellular nerve xenografts (ANX) has been proven more effective than the acellular nerve allografting. Besides, granulocyte colony-stimulating factor (G-CSF) can inhibit inflammation and apoptosis, and thus is conducive to the microenvironmental improvement of axonal regeneration. This study aims to investigate the joint effect of BMSCs-seeded ANX grafting and G-CSF administration, and explore the relevant mechanisms. Adult SD rats were divided into five groups randomly: ANX group, ANX combined with G-CSF group, BMSCs-laden ANX group, BMSCs-laden ANX combined with G-CSF group, and autograft group. Eight weeks after transplantation, the detection of praxiology and neuroelectrophysiology was conducted, and then the morphology of the regenerated nerves was analyzed. The inflammatory response and apoptosis in the nerve grafts as well as the expression of the growth-promoting factors in the regenerated tissues were further assayed. G-CSF intervention and BMSCs implanting synergistically promoted peripheral nerve regeneration and functional recovery following ANX bridging, and the restoration effect was matchable with that of the autologous nerve grafting. Moreover, local inflammation was alleviated, the apoptosis of the seeded BMSCs was decreased, and the levels of the neuromodulatory factors were elevated. In conclusion, the union application of BMSCs-implanted ANX and G-CSF ameliorated the niche of neurotization and advanced nerve regeneration substantially. The strategy achieved the favorable effectiveness as an alternative to the autotransplantation. K E Y W O R D Sacellular nerve xenograft, bone marrow stromal cells, granulocyte colony-stimulating factor, peripheral nerve regeneration, transplantation

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Double gene therapy with granulocyte colony-stimulating factor and vascular endothelial growth factor acts synergistically to improve nerve regeneration and functional outcome after sciatic nerve injury in mice

Cited by 35 publications

References 108 publications

Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

Combination Therapy of Human Umbilical Cord Blood Cells and Granulocyte Colony Stimulating Factor Reduces Histopathological and Motor Impairments in an Experimental Model of Chronic Traumatic Brain Injury

Sensory reinnervation of muscle spindles after repair of tibial nerve defects using autogenous vein grafts

Combination of BMSCs‐laden acellular nerve xenografts transplantation and G‐CSF administration promotes sciatic nerve regeneration

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