Required growth facilitators propel axon regeneration across complete spinal cord injury

Autor: Giovanni Coppola, Riki Kawaguchi, Chen Wang, Alexander L. Wollenberg, Michael V. Sofroniew, Sabry L. Barlatey, Zhigang He, Brian Kato, Grégoire Courtine, Jae H. Kim, Joshua E. Burda, Alexander M. Bernstein, Alexandra Rogers, Mark Anderson, Timothy J. Deming, Yan Ao, Nicholas D. James, Timothy M. O’Shea
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
medicine.medical_treatment
Neurodegenerative
Inbred C57BL
Regenerative Medicine
Mice
0302 clinical medicine
Neurotrophic factors
2.1 Biological and endogenous factors
Axon
Aetiology
Spinal Cord Injury
Spinal cord injury
Multidisciplinary
biology
Inbred Lew
Rehabilitation
Hydrogels
Electrophysiology
medicine.anatomical_structure
Neurological
Stem Cell Research - Nonembryonic - Non-Human
Female
Proteoglycans
Neuroglia
Neurotrophin
Spinal Cord Regeneration
Physical Injury - Accidents and Adverse Effects
General Science & Technology
1.1 Normal biological development and functioning
Article
03 medical and health sciences
Cicatrix
Underpinning research
medicine
Animals
Glial Cell Line-Derived Neurotrophic Factor
Traumatic Head and Spine Injury
Spinal Cord Injuries
Epidermal Growth Factor
Growth factor
Neurosciences
Recovery of Function
medicine.disease
Spinal cord
Stem Cell Research
Axons
Nerve Regeneration
Rats
Fibroblast Growth Factors
Mice
Inbred C57BL
030104 developmental biology
Rats
Inbred Lew
Astrocytes
biology.protein
Neuron
Laminin
Stromal Cells
Neuroscience
030217 neurology & neurosurgery
Zdroj: Nature
Nature, vol 561, iss 7723
ISSN: 1476-4687
Popis: Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after injury1-3, but efficient reversal of this regrowth failure remains elusive4. Here we show that three factorsthat are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity2,5-9, (ii) growth-supportive substrate10,11 and (iii) chemoattraction12,13-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI14,15; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor16,17 delivered via spatially and temporally controlled release from biomaterial depots18,19, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesioncores of non-neuraltissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
Databáze: OpenAIRE
Externí odkaz: