Use of a combination strategy to improve neuroprotection and neuroregeneration in a rat model of acute spinal cord injury

García, Elisa; Rodríguez-Barrera, Roxana; Buzoianu-Anguiano, Vinnitsa; Flores-Romero, Adrian; Malagón-Axotla, Emanuel; Guerrero-Godinez, Marco A.; Cruz-Castillo, Estefanía de la; Castillo-Carvajal, Laura C.; Rivas-González, Monserrat; Santiago-Tovar, Paola; Morales, Ivis; Borlongan, Cesar V.; Ibarra, Antonio

doi:10.4103/1673-5374.250627

Cited by 17 publications

(9 citation statements)

References 53 publications

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“…Mesenchymal stem cells (MSCs) have been widely studied as a therapy in neural injury models, including spinal cord injury (SCI), traumatic brain injury (TBI) and peripheral nerve injury [21][22][23][24][25]. Concerning the relationship between KLF7 and MSCs, very little is known.…”

Section: Introductionmentioning

confidence: 99%

KLF7 overexpression in bone marrow stromal stem cells graft transplantation promotes sciatic nerve regeneration

Zhu

Yue³

et al. 2019

J. Neural Eng.

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Objective. Our previous study demonstrated that the transcription factor, Krüppel-like Factor 7 (KLF7), stimulates axon regeneration following peripheral nerve injury. In the present study, we used a gene therapy approach to overexpress KLF7 in bone marrow-derived stem/stromal cells (BMSCs) as support cells, combined with acellular nerve allografts (ANAs) and determined the potential therapeutic efficacy of a KLF7-transfected BMSC nerve graft transplantation in a rodent model for sciatic nerve injury and repair. Approach. We efficiently transfected BMSCs with adeno-associated virus (AAV)-KLF7, which were then seeded in ANAs for bridging sciatic nerve defects. Main results. KLF7 overexpression promotes proliferation, survival, and Schwann-like cell differentiation of BMSCs in vitro. In vivo, KLF7 overexpression promotes transplanted BMSCs survival and myelinated fiber regeneration in regenerating ANAs; however, KLF7 did not improve Schwann-like cell differentiation of BMSCs within in the nerve grafts. KLF7-BMSCs significantly upregulated expression and secretion of neurotrophic factors by BMSCs, including nerve growth factor, ciliary neurotrophic factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in regenerating ANA. KLF7-BMSCs also improved motor axon regeneration, and subsequent neuromuscular innervation and prevention of muscle atrophy. These benefits were associated with increased motor functional recovery of regenerating ANAs. Significance. Our findings suggest that KLF7-BMSCs promoted peripheral nerve axon regeneration and myelination, and ultimately, motor functional recovery. The mechanism of KLF7 action may be related to its ability to enhance transplanted BMSCs survival and secrete neurotrophic factors rather than Schwann-like cell differentiation. This study provides novel foundational data connecting the benefits of KLF7 in neural injury and repair to BMSC biology and function, and demonstrates a potential combination approach for the treatment of injured peripheral nerve via nerve graft transplant.

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Section: Introductionmentioning

confidence: 99%

KLF7 overexpression in bone marrow stromal stem cells graft transplantation promotes sciatic nerve regeneration

Zhu

Yue³

et al. 2019

J. Neural Eng.

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“…This alteration increases the susceptibility to develop various pathologies that compromise the stability and life of SCI patients 16,43,44 . Several studies have elucidated that, in addition to the important role of T-cells in response to any infectious disease, they also participate in processes related to neuroprotection and neuroregeneration after injury 18,19,45 . Nevertheless, these cells decrease after SCI because of ISS, as reported by Riegger and coworkers 3 .…”

Section: Discussionmentioning

confidence: 99%

Supplementation With Vitamin E, Zinc, Selenium, and Copper Re-Establishes T-Cell Function and Improves Motor Recovery in a Rat Model of Spinal Cord Injury

et al. 2022

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Spinal cord injury (SCI) causes a dysfunction of sympathetic nervous system innervation that affects the immune system, leading to immunosuppression syndrome (ISS) and contributing to patient degeneration and increased risk of several infections. A possible therapeutic strategy that could avoid further patient deterioration is the supplementation with Vitamin E or trace elements, such as Zinc, Selenium, and Copper, which individually promotes T-cell differentiation and proliferative responses. For this reason, the aim of the present study was to evaluate whether Vitamin E, Zinc, Selenium, and Copper supplementation preserves the number of T-lymphocytes and improves their proliferative function after traumatic SCI. Sprague–Dawley female rats were subjected to moderate SCI and then randomly allocated into three groups: (1) SCI + supplements; (2) SCI + vehicle (olive oil and phosphate-buffered saline); and (3) sham-operated rats. In all rats, the intervention was initiated 15 min after SCI and then administered daily until the end of study. Locomotor recovery was assessed at 7 and 15 days after SCI. At 15 days after supplementation, the quantification of the number of T-cells and its proliferation function were examined. Our results showed that the SCI + supplements group presented a significant improvement in motor recovery at 7 and 15 days after SCI. In addition, this group showed a better T-cell number and proliferation rate than that observed in the group with SCI + vehicle. Our findings suggest that Vitamin E, Zinc, Selenium, and Copper supplementation could be part of a therapy for patients suffering from acute SCI, helping to preserve T-cell function, avoiding complications, and promoting a better motor recovery. All procedures were approved by the Animal Bioethics and Welfare Committee (Approval No. 201870; CSNBTBIBAJ 090812960).

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“…Previous studies in SCI models have shown that INDP is a promising therapeutic strategy to promote neuroprotection and neural restauration. These beneficial effects have been observed when INDP is administered in both acute and chronic phases of SCI (5,10). Therefore, our purpose is to improve its protective and restorative benefits by combining INDP whit other successful therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

“…Infiltration of inflammatory cells has been correlated with the amount of tissue damaged after injury. However, it has been shown that the presence of inflammatory cells is essential for neuroprotection (4,5) and regeneration (6,7) of the SC, where its action depends on the effects exerted by autorreactive Central Nervous System (CNS) T-cells which are part of an autoimmune response developed after injury (4).…”

Section: Introductionmentioning

confidence: 99%

“…PA is a physiological mechanism induced after SCI that could be boosted by immunizing with neural-derived peptides (INDP), a therapeutic strategy that requires the use of peptides such as A91 to induce PA. A91 is a peptide derived from the immunogenic sequence (87-99) of the myelin basic protein (MBP), the most immunogenic protein in the CNS. Activating T-cells by means of A91 87−99 peptide, induces a Th2 response, which stimulates microglia to its differentiation to an M2 phenotype, resulting in a micro-environment with lower production of free radicals, improved motor recovery, among other neuroprotective mechanisms (5,8,9) as well as axonal regeneration (7,10). This therapeutic strategy has rendered encouraging results both, in acute and chronic SCI, being the chronic one the most difficult stage of injury to carry out a therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

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Use of a Combination Strategy to Improve Morphological and Functional Recovery in Rats With Chronic Spinal Cord Injury

et al. 2020

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Immunization with neural derived peptides (INDP), as well as scar removal (SR) and the use of matrices with bone marrow-mesenchymal stem cells (MSCs), have been studied separately and proven to induce a functional and morphological improvement after spinal cord injury (SCI). Herein, we evaluated the therapeutic effects of INDP combined with SR and a fibrin glue matrix (FGM) with MSCs (FGM-MSCs), on motor recovery, axonal regeneration-associated molecules and cytokine expression, axonal regeneration (catecholaminergic and serotonergic fibers), and the induction of neurogenesis after a chronic SCI. For this purpose, female adult Sprague-Dawley rats were subjected to SCI, 60 days after lesion, rats were randomly distributed in four groups: (1) Rats immunized with complete Freund's adjuvant + PBS (vehicle; PBS-I); (2) Rats with SR+ FGM-MSCs; (3) Rats with SR+ INDP + FGM-MSCs; (4) Rats only with INDP. Afterwards, we evaluated motor recovery using the BBB locomotor test. Sixty days after the therapy, protein expression of TNFα, IL-4, IL-10, BDNF, and GAP-43 were evaluated using ELISA assay. The number of catecholaminergic and serotonergic fibers were also determined. Neurogenesis was evaluated through immunofluorescence. The results show that treatment with INDP alone significantly increased motor recovery, anti-inflammatory cytokines, regeneration-associated molecules, axonal regeneration, and neurogenesis when compared to the rest of the groups. Our findings suggest that the combination therapy (SR + INDP + FGM-MSCs) modifies the non-permissive microenvironment post SCI, but it is not capable of inducing an appropriate axonal regeneration or neurogenesis when compared to the treatment with INDP alone.

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Use of a combination strategy to improve neuroprotection and neuroregeneration in a rat model of acute spinal cord injury

Cited by 17 publications

References 53 publications

KLF7 overexpression in bone marrow stromal stem cells graft transplantation promotes sciatic nerve regeneration

KLF7 overexpression in bone marrow stromal stem cells graft transplantation promotes sciatic nerve regeneration

Supplementation With Vitamin E, Zinc, Selenium, and Copper Re-Establishes T-Cell Function and Improves Motor Recovery in a Rat Model of Spinal Cord Injury

Use of a Combination Strategy to Improve Morphological and Functional Recovery in Rats With Chronic Spinal Cord Injury

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