Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury
Abstract Background Spinal cord injury (SCI) is a devastating condition mainly deriving from a traumatic damage of the spinal cord (SC). Immune cells and endogenous SC-neural stem cells (SC-NSCs) play a critical role in wound healing processes, although both are ineffective to completely restore tis...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1085-9 |
| _version_ | 1818557318486294528 |
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| author | Melania Cusimano Elena Brambilla Alessia Capotondo Donatella De Feo Antonio Tomasso Giancarlo Comi Patrizia D’Adamo Luca Muzio Gianvito Martino |
| author_facet | Melania Cusimano Elena Brambilla Alessia Capotondo Donatella De Feo Antonio Tomasso Giancarlo Comi Patrizia D’Adamo Luca Muzio Gianvito Martino |
| author_sort | Melania Cusimano |
| collection | DOAJ |
| description | Abstract Background Spinal cord injury (SCI) is a devastating condition mainly deriving from a traumatic damage of the spinal cord (SC). Immune cells and endogenous SC-neural stem cells (SC-NSCs) play a critical role in wound healing processes, although both are ineffective to completely restore tissue functioning. The role of SC-NSCs in SCI and, in particular, whether such cells can interplay with the immune response are poorly investigated issues, although mechanisms governing such interactions might open new avenues to develop novel therapeutic approaches. Methods We used two transgenic mouse lines to trace as well as to kill SC-NSCs in mice receiving SCI. We used Nestin CreERT2 mice to trace SC-NSCs descendants in the spinal cord of mice subjected to SCI. While mice carrying the suicide gene thymidine kinase (TK) along with the GFP reporter, under the control of the Nestin promoter regions (NestinTK mice) were used to label and selectively kill SC-NSCs. Results We found that SC-NSCs are capable to self-activate after SCI. In addition, a significant worsening of clinical and pathological features of SCI was observed in the NestinTK mice, upon selective ablation of SC-NSCs before the injury induction. Finally, mice lacking in SC-NSCs and receiving SCI displayed reduced levels of different neurotrophic factors in the SC and significantly higher number of M1-like myeloid cells. Conclusion Our data show that SC-NSCs undergo cell proliferation in response to traumatic spinal cord injury. Mice lacking SC-NSCs display overt microglia activation and exaggerate expression of pro-inflammatory cytokines. The absence of SC-NSCs impaired functional recovery as well as neuronal and oligodendrocyte cell survival. Collectively our data indicate that SC-NSCs can interact with microglia/macrophages modulating their activation/responses and that such interaction is importantly involved in mechanisms leading tissue recovery. |
| first_indexed | 2024-12-13T23:57:56Z |
| format | Article |
| id | doaj.art-b9368f91e60b460da87e2902e93fee74 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-13T23:57:56Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b9368f91e60b460da87e2902e93fee742022-12-21T23:26:29ZengBMCJournal of Neuroinflammation1742-20942018-02-0115111410.1186/s12974-018-1085-9Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injuryMelania Cusimano0Elena Brambilla1Alessia Capotondo2Donatella De Feo3Antonio Tomasso4Giancarlo Comi5Patrizia D’Adamo6Luca Muzio7Gianvito Martino8Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific InstituteNeuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific InstituteNeuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific InstituteNeuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific InstituteNeuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific InstituteDepartment of Neurology, Institute of Experimental Neurology (INSPE), Vita Salute San Raffaele UniversityMolecular Genetics of Intellectual Disabilities Unit, Division of Neuroscience at San Raffaele Scientific InstituteNeuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific InstituteNeuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific InstituteAbstract Background Spinal cord injury (SCI) is a devastating condition mainly deriving from a traumatic damage of the spinal cord (SC). Immune cells and endogenous SC-neural stem cells (SC-NSCs) play a critical role in wound healing processes, although both are ineffective to completely restore tissue functioning. The role of SC-NSCs in SCI and, in particular, whether such cells can interplay with the immune response are poorly investigated issues, although mechanisms governing such interactions might open new avenues to develop novel therapeutic approaches. Methods We used two transgenic mouse lines to trace as well as to kill SC-NSCs in mice receiving SCI. We used Nestin CreERT2 mice to trace SC-NSCs descendants in the spinal cord of mice subjected to SCI. While mice carrying the suicide gene thymidine kinase (TK) along with the GFP reporter, under the control of the Nestin promoter regions (NestinTK mice) were used to label and selectively kill SC-NSCs. Results We found that SC-NSCs are capable to self-activate after SCI. In addition, a significant worsening of clinical and pathological features of SCI was observed in the NestinTK mice, upon selective ablation of SC-NSCs before the injury induction. Finally, mice lacking in SC-NSCs and receiving SCI displayed reduced levels of different neurotrophic factors in the SC and significantly higher number of M1-like myeloid cells. Conclusion Our data show that SC-NSCs undergo cell proliferation in response to traumatic spinal cord injury. Mice lacking SC-NSCs display overt microglia activation and exaggerate expression of pro-inflammatory cytokines. The absence of SC-NSCs impaired functional recovery as well as neuronal and oligodendrocyte cell survival. Collectively our data indicate that SC-NSCs can interact with microglia/macrophages modulating their activation/responses and that such interaction is importantly involved in mechanisms leading tissue recovery.http://link.springer.com/article/10.1186/s12974-018-1085-9Spinal cord injuryEndogenous neural stem cellsNeurotrophic factorsInflammation |
| spellingShingle | Melania Cusimano Elena Brambilla Alessia Capotondo Donatella De Feo Antonio Tomasso Giancarlo Comi Patrizia D’Adamo Luca Muzio Gianvito Martino Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury Journal of Neuroinflammation Spinal cord injury Endogenous neural stem cells Neurotrophic factors Inflammation |
| title | Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury |
| title_full | Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury |
| title_fullStr | Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury |
| title_full_unstemmed | Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury |
| title_short | Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury |
| title_sort | selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury |
| topic | Spinal cord injury Endogenous neural stem cells Neurotrophic factors Inflammation |
| url | http://link.springer.com/article/10.1186/s12974-018-1085-9 |
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