Microglial cells, which are highly plastic, immediately respond to any change in the microenvironment by becoming activated and shifting the phenotype toward neurotoxicity or neuroprotection. The polarization of microglia/macrophages after spinal cord injury (SCI) seems to be a dynamic process and can change depending on the microenvironment, stage, course, and severity of the posttraumatic process. Effective methods to modulate microglia toward a neuroprotective phenotype in order to stimulate neuroregeneration are actively sought for. In this context, available approaches that can selectively impact the polarization of microglia/macrophages regulate synthesis of trophic factors and cytokines/chemokines in them, and their phagocytic function and effects on the course and outcome of SCI are discussed in this review.
Our study of the changes in cytokine profile in blood serum and in the spinal cord after traumatic spinal cord injury (SCI) has shown that an inflammatory reaction and immunological response are not limited to the CNS, but widespread. This fact was confirmed by changes detected in a cytokine profile in blood serum samples [MIP-1α, interleukin 1 (IL-1) α, IL-2, IL-5, IL-1β, MCP-1, RANTES]. There were also changes in the levels of MIP-1α, IL-1α, IL-2, IL-5, IL-18, GM-colony-stimulating factor, IL-17α, IFN-γ, IL-10, IL-13, MCP-1, and GRO KC CINC-1 in samples of the rat injured spinal cord. The results underscore the complex cytokine network imbalance exhibited after SCI and show significant changes in the concentrations of 14 cytokines/chemokines with different inflammatory and immunological activities.
The use of stem and progenitor cells to restore damaged organs and tissues, in particular, the central nervous system, is currently considered a most promising therapy in regenerative medicine. At the same time, another approach aimed at stimulating regeneration with the use of stem cells encapsulated into a biopolymer matrix and capable of creating a specific microenvironment for the implanted cells similar to the natural extracellular matrix is under active development. Here, we study effects of the application of adipose-derived mesenchymal stem cells (AD-MSCs) combined with a fibrin matrix on post-traumatic reactions in the spinal cord in rats. The AD-MSC application is found to exert a positive impact on the functional and structural recovery after spinal cord injury (SCI) that has been confirmed by the results of behavioral/electrophysiological and morphometric studies demonstrating reduced area of abnormal cavities and enhanced tissue retention in the site of injury. Immunohistochemical and real-time PCR analyses provide evidence that AD-MSC application decreases the GFAP expression in the area of SCI that might indicate the reduction of astroglial activation. Our results also demonstrate that AD-MSC application contributes to marked upregulation of PDGFβR and HSPA1b mRNA expression and decrease of Iba1 expression at the site of the central canal. Thus, the application of AD-MSCs combined with fibrin matrix at the site of SCI during the subacute period can stimulate important mechanisms of nervous tissue regeneration and should be further developed for clinical applications.
The use of extracellular vesicles (EVs) as cell free therapy is a promising approach to stimulate tissue regeneration including that of the nervous system. EVs transfer bioactive proteins and lipids, RNA and microRNAs, which play a relevant role in EV-mediated intercellular communication. The immunomodulatory, anti-inflammatory, and neuroprotective effects of mesenchymal stem cells-derived EVs have been well studied, knowledge of this paracrine mechanism and the availability of these cells, positions mesenchymal stem cells as a potential source of EVs for cell free therapy for a variety of regenerative and nervous system disorders. In this review, we focus on the immunomodulatory and neuroprotective effects of stem cells-derived EVs within in vitro and in vivo models of nerve disorders.
Here, we provide a first comparative study of the therapeutic potential of allogeneic mesenchymal stem cells derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), and dental pulp (DP-MSCs) embedded in fibrin matrix, in small (rat) and large (pig) spinal cord injury (SCI) models during subacute period of spinal contusion. Results of behavioral, electrophysiological, and histological assessment as well as immunohistochemistry and real-time polymerase chain reaction analysis suggest that application of AD-MSCs combined with a fibrin matrix within the subacute period in rats (2 weeks after injury), provides significantly higher post-traumatic regeneration compared to a similar application of BM-MSCs or DP-MSCs. Within the rat model, use of AD-MSCs resulted in a marked change in: (1) restoration of locomotor activity and conduction along spinal axons; (2) reduction of post-traumatic cavitation and enhancing tissue retention; and (3) modulation of microglial and astroglial activation. The effect of an autologous application of AD-MSCs during the subacute period after spinal contusion was also confirmed in pigs (6 weeks after injury). Effects included: (1) partial restoration of the somatosensory spinal pathways; (2) reduction of post-traumatic cavitation and enhancing tissue retention; and (3) modulation of astroglial activation in dorsal root entry zone. However, pigs only partially replicated the findings observed in rats. Together, these results indicate application of AD-MSCs embedded in fibrin matrix at the site of SCI during the subacute period can facilitate regeneration of nervous tissue in rats and pigs. These results, for the first time, provide robust support for the use of AD-MSC to treat subacute SCI.
Study design: Experimental study. Objective: To evaluate the treatment of spinal cord injury with glial cell-derived neurotrophic factor (GDNF) delivered using an adenoviral vector (AdV-GDNF group) in comparison with treatment performed using human umbilical cord blood mononuclear cells (UCB-MCs)-transduced with an adenoviral vector carrying the GDNF gene (UCB-MCs+AdV-GDNF group) in rat. Setting: Kazan, Russian Federation. Methods: We examined the efficacy of AdV-GDNF and UCB-MCs+AdV-GDNF therapy by conducting behavioral tests on the animals and morphometric studies on the spinal cord, performing immunofluorescence analyses on glial cells, investigating the survival and migration potential of UCB-MCs, and evaluating the expression of the recombinant GDNF gene. Results: At the 30th postoperative day, equal positive locomotor recovery was observed after both direct and cell-based GDNF therapy. However, after UCB-MCs-mediated GDNF therapy, the area of preserved tissue and the number of spared myelinated fibers were higher than those measured after direct GDNF gene therapy. Moreover, we observed distinct changes in the populations of glial cells; expression patterns of the specific markers for astrocytes (GFAP, S100B and AQP4), oligodendrocytes (PDGFαR and Cx47) and Schwann cells (P0) differed in various areas of the spinal cord of rats treated with AdV-GDNF and UCB-MCs+AdV-GDNF. Conclusion: The differences detected in the AdV-GDNF and UCB-MCs+AdV-GDNF groups could be partially explained by the action of UCB-MCs. We discuss the insufficiency and the advantages of these two methods of GDNF gene delivery into the spinal cord after traumatic injury. INTRODUCTIONSpinal cord injury (SCI) leads to complex pathological changes that include the death of neurons and glial cells and the demyelination and degeneration of nerve fibers. The limited growth capacity of mature central nervous system (CNS) neurons and the non-permissive environment of the CNS for axon regrowth are the main factors responsible for the little or no regeneration toward targets displayed by injured axons and for the permanent functional deficit observed after SCI. One promising approach for preventing neurodegeneration involves locally treating the site of injury in order to increase the expression of neurotrophic factors. Exploiting the stimulatory effects of neurotrophic factors on neuroregeneration appears to also be useful for SCI treatment, and one neurotrophic factor that is particularly suitable for SCI treatment is glial cell-derived neurotrophic factor (GDNF). GDNF is a member of the TGF-β superfamily that binds to the receptor GFRα1 and upregulates several signaling pathways; these pathways include those involving intracellular RAS/extracellular signalregulated kinase, phosphatidylinositol 3-kinase/AKT, p38 mitogen-
Cell-based technologies are used as a therapeutic strategy in spinal cord injury (SCI). Mesenchymal stem cells (MSCs), which secrete various neurotrophic factors and cytokines, have immunomodulatory, anti-apoptotic and anti-inflammatory effects, modulate reactivity/phenotype of astrocytes and the microglia, thereby promoting neuroregeneration seem to be the most promising. The therapeutic effect of MSCs is due to a paracrine mechanism of their action, therefore the survival of MSCs and their secretory phenotype is of particular importance. Nevertheless, these data are not always reported in efficacy studies of MSC therapy in SCI. Here, we provide a review with summaries of preclinical trials data evaluating the efficacy of MSCs in animal models of SCI. Based on the data collected, we have tried (1) to establish the behavior of MSCs after transplantation in SCI with an evaluation of cell survival, migration potential, distribution in the area of injured and intact tissue and possible differentiation; (2) to determine the effects MSCs on neuronal microenvironment and correlate them with the efficacy of functional recovery in SCI; (3) to ascertain the conditions under which MSCs demonstrate their best survival and greatest efficacy.
Amyotrophic lateral sclerosis (ALS) is an incurable, chronic, fatal neuro-degenerative disease characterized by progressive loss of moto-neurons and paralysis of skeletal muscles. Reactivating dysfunctional areas is under earnest investigation utilizing various approaches. Here we present an innovative gene-cell construct aimed at reviving inert structure and function. Human umbilical cord blood cells (hUCBCs) transduced with adeno-viral vectors encoding human VEGF, GDNF and/or NCAM genes were transplanted into transgenic ALS mice models. Significant improvement in behavioral performance (open-field and grip-strength tests), as well as increased life-span was observed in rodents treated with NCAM-VEGF or NCAM-GDNF co-transfected cells. Active trans-gene expression was found in the spinal cord of ALS mice 10 weeks after delivering genetically modified hUCBCs, and cells were detectable even 5 months following transplantation. Our gene-cell therapy model yielded prominent symptomatic control and prolonged life-time in ALS. Incredible survivability of xeno-transpanted cells was also observed without any immune-suppression. These results suggest that engineered hUCBCs may offer effective gene-cell therapy in ALS.
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