Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury
Traumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the s...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Mary Ann Liebert
2021-01-01
|
| Series: | Neurotrauma Reports |
| Subjects: | |
| Online Access: | https://www.liebertpub.com/doi/full/10.1089/NEUR.2020.0016 |
| _version_ | 1797346233398853632 |
|---|---|
| author | Ashley K. Pringle Elshadaie Solomon Benjamin J. Coles Brandon R. Desousa Anan Shtaya Shyam Gajavelli Nedal Dabab Malik J. Zaben Diederik O. Bulters M. Ross Bullock Aminul I. Ahmed |
| author_facet | Ashley K. Pringle Elshadaie Solomon Benjamin J. Coles Brandon R. Desousa Anan Shtaya Shyam Gajavelli Nedal Dabab Malik J. Zaben Diederik O. Bulters M. Ross Bullock Aminul I. Ahmed |
| author_sort | Ashley K. Pringle |
| collection | DOAJ |
| description | Traumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the sonic hedgehog pathway, a key NSC regulatory pathway, could lead to functional improvement. We assessed sonic hedgehog (Shh) protein levels in the cerebrospinal fluid (CSF) of patients with TBI. Using the cortical contusion injury (CCI) model in rodents, we used pharmacological modulators of Shh signaling to assess cell proliferation within the injured cortex using the marker 5-Ethynyl-2?-deoxyuridine (EdU); 50mg/mL. The phenotype of proliferating cells was determined and quantified. Motor function was assessed using the rotarod test. In patients with TBI there is a reduction of Shh protein in CSF compared with control patients. In rodents, following a severe CCI, quiescent cells become activated. Pharmacologically modulating the Shh signaling pathway leads to changes in the number of newly proliferating injury-induced cells. Upregulation of Shh signaling with Smoothened agonist (SAG) results in an increase of newly proliferating cells expressing glial fibrillary acidic protein (GFAP), whereas the Shh signaling inhibitor cyclopamine leads to a reduction. Some cells expressed doublecortin (DCX) but did not mature into neurons. The SAG-induced increase in proliferation is associated with improved recovery of motor function. Localized restoration of Shh in the injured rodent brain, via increased Shh signaling, has the potential to sustain endogenous cell proliferation and the mitigation of TBI-induced motor deficits albeit without the neuronal differentiation. |
| first_indexed | 2024-03-08T11:29:03Z |
| format | Article |
| id | doaj.art-718aa45de3774383adfb2b45270a201e |
| institution | Directory Open Access Journal |
| issn | 2689-288X |
| language | English |
| last_indexed | 2024-03-08T11:29:03Z |
| publishDate | 2021-01-01 |
| publisher | Mary Ann Liebert |
| record_format | Article |
| series | Neurotrauma Reports |
| spelling | doaj.art-718aa45de3774383adfb2b45270a201e2024-01-26T04:22:54ZengMary Ann LiebertNeurotrauma Reports2689-288X2021-01-0121273810.1089/NEUR.2020.0016Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion InjuryAshley K. PringleElshadaie SolomonBenjamin J. ColesBrandon R. DesousaAnan ShtayaShyam GajavelliNedal DababMalik J. ZabenDiederik O. BultersM. Ross BullockAminul I. AhmedTraumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the sonic hedgehog pathway, a key NSC regulatory pathway, could lead to functional improvement. We assessed sonic hedgehog (Shh) protein levels in the cerebrospinal fluid (CSF) of patients with TBI. Using the cortical contusion injury (CCI) model in rodents, we used pharmacological modulators of Shh signaling to assess cell proliferation within the injured cortex using the marker 5-Ethynyl-2?-deoxyuridine (EdU); 50mg/mL. The phenotype of proliferating cells was determined and quantified. Motor function was assessed using the rotarod test. In patients with TBI there is a reduction of Shh protein in CSF compared with control patients. In rodents, following a severe CCI, quiescent cells become activated. Pharmacologically modulating the Shh signaling pathway leads to changes in the number of newly proliferating injury-induced cells. Upregulation of Shh signaling with Smoothened agonist (SAG) results in an increase of newly proliferating cells expressing glial fibrillary acidic protein (GFAP), whereas the Shh signaling inhibitor cyclopamine leads to a reduction. Some cells expressed doublecortin (DCX) but did not mature into neurons. The SAG-induced increase in proliferation is associated with improved recovery of motor function. Localized restoration of Shh in the injured rodent brain, via increased Shh signaling, has the potential to sustain endogenous cell proliferation and the mitigation of TBI-induced motor deficits albeit without the neuronal differentiation.https://www.liebertpub.com/doi/full/10.1089/NEUR.2020.0016cerebral cortexendogenous stem cellsmotor recoverysonic hedgehogtraumatic brain injury |
| spellingShingle | Ashley K. Pringle Elshadaie Solomon Benjamin J. Coles Brandon R. Desousa Anan Shtaya Shyam Gajavelli Nedal Dabab Malik J. Zaben Diederik O. Bulters M. Ross Bullock Aminul I. Ahmed Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury Neurotrauma Reports cerebral cortex endogenous stem cells motor recovery sonic hedgehog traumatic brain injury |
| title | Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury |
| title_full | Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury |
| title_fullStr | Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury |
| title_full_unstemmed | Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury |
| title_short | Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury |
| title_sort | sonic hedgehog signaling promotes peri lesion cell proliferation and functional improvement after cortical contusion injury |
| topic | cerebral cortex endogenous stem cells motor recovery sonic hedgehog traumatic brain injury |
| url | https://www.liebertpub.com/doi/full/10.1089/NEUR.2020.0016 |
| work_keys_str_mv | AT ashleykpringle sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT elshadaiesolomon sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT benjaminjcoles sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT brandonrdesousa sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT ananshtaya sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT shyamgajavelli sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT nedaldabab sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT malikjzaben sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT diederikobulters sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT mrossbullock sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury AT aminuliahmed sonichedgehogsignalingpromotesperilesioncellproliferationandfunctionalimprovementaftercorticalcontusioninjury |