Melania Cusimano1, Elena Brambilla1, Alessia Capotondo1, Donatella De Feo1, Antonio Tomasso1, Giancarlo Comi2, Patrizia D'Adamo3, Luca Muzio4, Gianvito Martino5. 1. Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. 2. Department of Neurology, Institute of Experimental Neurology (INSPE), Vita Salute San Raffaele University, 20132, Milan, Italy. 3. Molecular Genetics of Intellectual Disabilities Unit, Division of Neuroscience at San Raffaele Scientific Institute, Milan, Italy. 4. Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. muzio.luca@hsr.it. 5. Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. gianvito.martino@hsr.it.
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.
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 transgenicmouse 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 (NestinTKmice) 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 NestinTKmice, 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.
Authors: Fanie Barnabé-Heider; Christian Göritz; Hanna Sabelström; Hirohide Takebayashi; Frank W Pfrieger; Konstantinos Meletis; Jonas Frisén Journal: Cell Stem Cell Date: 2010-10-08 Impact factor: 24.633
Authors: Leah A Mawhinney; Sakina G Thawer; Wei-Yang Lu; Nico van Rooijen; Lynne C Weaver; Arthur Brown; Gregory A Dekaban Journal: J Neuropathol Exp Neurol Date: 2012-03 Impact factor: 3.685
Authors: D Michele Basso; Lesley C Fisher; Aileen J Anderson; Lyn B Jakeman; Dana M McTigue; Phillip G Popovich Journal: J Neurotrauma Date: 2006-05 Impact factor: 5.269