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Neuroprotection and immunomodulation following intraspinal axotomy of motoneurons by treatment with adult mesenchymal stem cells.
J Neuroinflammation. 2018 Aug 14; 15(1):230.JN

Abstract

BACKGROUND

Treatment of spinal cord injury is dependent on neuronal survival, appropriate synaptic circuit preservation, and inflammatory environment management. In this sense, mesenchymal stem cell (MSC) therapy is a promising tool that can reduce glial reaction and provide trophic factors to lesioned neurons.

METHODS

Lewis adult female rats were submitted to a unilateral ventral funiculus cut at the spinal levels L4, L5, and L6. The animals were divided into the following groups: IA (intramedullary axotomy), IA + DMEM (Dulbecco's modified Eagle's medium), IA + FS (fibrin sealant), IA + MSC (106 cells), and IA + FS + MSC (106 cells). Seven days after injury, qPCR (n = 5) was performed to assess gene expression of VEGF, BDNF, iNOS2, arginase-1, TNF-α, IL-1β, IL-6, IL-10, IL-4, IL-13, and TGF-β. The cellular infiltrate at the lesion site was analyzed by hematoxylin-eosin (HE) staining and immunohistochemistry (IH) for Iba1 (microglia and macrophage marker) and arginase-1. Fourteen days after injury, spinal alpha motor neurons (MNs), evidenced by Nissl staining (n = 5), were counted. For the analysis of astrogliosis in spinal lamina IX and synaptic detachment around lesioned motor neurons (GAP-43-positive cells), anti-GFAP and anti-synaptophysin immunohistochemistry (n = 5) was performed, respectively. Twenty-eight days after IA, the gait of the animals was evaluated by the walking track test (CatWalk; n = 7).

RESULTS

The site of injury displayed strong monocyte infiltration, containing arginase-1-expressing macrophages. The FS-treated group showed upregulation of iNOS2, arginase-1, proinflammatory cytokine (TNF-α and IL-1β), and antiinflammatory cytokine (IL-10, IL-4, and IL-13) expression. Thus, FS enhanced early macrophage recruitment and proinflammatory cytokine expression, which accelerated inflammation. Rats treated with MSCs displayed high BDNF-positive immunolabeling, suggesting local delivery of this neurotrophin to lesioned motoneurons. This BDNF expression may have contributed to the increased neuronal survival and synapse preservation and decreased astrogliosis observed 14 days after injury. At 28 days after lesion, gait recovery was significantly improved in MSC-treated animals compared to that in the other groups.

CONCLUSIONS

Overall, the present data demonstrate that MSC therapy is neuroprotective and, when associated with a FS, shifts the immune response to a proinflammatory profile.

Authors+Show Affiliations

Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil.Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil.Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil.Center for the Study of Venoms and Venomous Animals (CEVAP), São Paulo State University (UNESP), Botucatu, SP, Brazil.Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil. alroliv@unicamp.br.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30107848

Citation

Spejo, A B., et al. "Neuroprotection and Immunomodulation Following Intraspinal Axotomy of Motoneurons By Treatment With Adult Mesenchymal Stem Cells." Journal of Neuroinflammation, vol. 15, no. 1, 2018, p. 230.
Spejo AB, Chiarotto GB, Ferreira ADF, et al. Neuroprotection and immunomodulation following intraspinal axotomy of motoneurons by treatment with adult mesenchymal stem cells. J Neuroinflammation. 2018;15(1):230.
Spejo, A. B., Chiarotto, G. B., Ferreira, A. D. F., Gomes, D. A., Ferreira, R. S., Barraviera, B., & Oliveira, A. L. R. (2018). Neuroprotection and immunomodulation following intraspinal axotomy of motoneurons by treatment with adult mesenchymal stem cells. Journal of Neuroinflammation, 15(1), 230. https://doi.org/10.1186/s12974-018-1268-4
Spejo AB, et al. Neuroprotection and Immunomodulation Following Intraspinal Axotomy of Motoneurons By Treatment With Adult Mesenchymal Stem Cells. J Neuroinflammation. 2018 Aug 14;15(1):230. PubMed PMID: 30107848.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotection and immunomodulation following intraspinal axotomy of motoneurons by treatment with adult mesenchymal stem cells. AU - Spejo,A B, AU - Chiarotto,G B, AU - Ferreira,A D F, AU - Gomes,D A, AU - Ferreira,R S,Jr AU - Barraviera,B, AU - Oliveira,A L R, Y1 - 2018/08/14/ PY - 2018/05/10/received PY - 2018/08/02/accepted PY - 2018/8/16/entrez PY - 2018/8/16/pubmed PY - 2019/5/21/medline KW - Astrogliosis KW - Funiculus cut KW - Immunomodulation KW - Microglial reaction KW - Motoneuron KW - Spinal cord SP - 230 EP - 230 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 15 IS - 1 N2 - BACKGROUND: Treatment of spinal cord injury is dependent on neuronal survival, appropriate synaptic circuit preservation, and inflammatory environment management. In this sense, mesenchymal stem cell (MSC) therapy is a promising tool that can reduce glial reaction and provide trophic factors to lesioned neurons. METHODS: Lewis adult female rats were submitted to a unilateral ventral funiculus cut at the spinal levels L4, L5, and L6. The animals were divided into the following groups: IA (intramedullary axotomy), IA + DMEM (Dulbecco's modified Eagle's medium), IA + FS (fibrin sealant), IA + MSC (106 cells), and IA + FS + MSC (106 cells). Seven days after injury, qPCR (n = 5) was performed to assess gene expression of VEGF, BDNF, iNOS2, arginase-1, TNF-α, IL-1β, IL-6, IL-10, IL-4, IL-13, and TGF-β. The cellular infiltrate at the lesion site was analyzed by hematoxylin-eosin (HE) staining and immunohistochemistry (IH) for Iba1 (microglia and macrophage marker) and arginase-1. Fourteen days after injury, spinal alpha motor neurons (MNs), evidenced by Nissl staining (n = 5), were counted. For the analysis of astrogliosis in spinal lamina IX and synaptic detachment around lesioned motor neurons (GAP-43-positive cells), anti-GFAP and anti-synaptophysin immunohistochemistry (n = 5) was performed, respectively. Twenty-eight days after IA, the gait of the animals was evaluated by the walking track test (CatWalk; n = 7). RESULTS: The site of injury displayed strong monocyte infiltration, containing arginase-1-expressing macrophages. The FS-treated group showed upregulation of iNOS2, arginase-1, proinflammatory cytokine (TNF-α and IL-1β), and antiinflammatory cytokine (IL-10, IL-4, and IL-13) expression. Thus, FS enhanced early macrophage recruitment and proinflammatory cytokine expression, which accelerated inflammation. Rats treated with MSCs displayed high BDNF-positive immunolabeling, suggesting local delivery of this neurotrophin to lesioned motoneurons. This BDNF expression may have contributed to the increased neuronal survival and synapse preservation and decreased astrogliosis observed 14 days after injury. At 28 days after lesion, gait recovery was significantly improved in MSC-treated animals compared to that in the other groups. CONCLUSIONS: Overall, the present data demonstrate that MSC therapy is neuroprotective and, when associated with a FS, shifts the immune response to a proinflammatory profile. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/30107848/Neuroprotection_and_immunomodulation_following_intraspinal_axotomy_of_motoneurons_by_treatment_with_adult_mesenchymal_stem_cells_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1268-4 DB - PRIME DP - Unbound Medicine ER -