title: Astrocyte scar formation aids central nervous system axon regeneration.
abstract: Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Anderson
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Burda
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ao
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: O'Shea
authors.affiliation: Departments of Psychiatry and Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1761, USA.
authors.forename: Riki
authors.initials: R
authors.lastname: Kawaguchi
authors.affiliation: Departments of Psychiatry and Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1761, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1751, USA.
authors.forename: Baljit S
authors.initials: BS
authors.lastname: Khakh
authors.affiliation: Departments of Bioengineering, Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095-1600, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Deming
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001369:Axons / Q000502:physiology*; D002490:Central Nervous System / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis; D002921:Cicatrix / Q000473:pathology* / Q000517:prevention & control; D005260:Female; D023281:Genomics; D051379:Mice; D008954:Models, Biological; D009416:Nerve Regeneration; D015203:Reproducibility of Results; D013119:Spinal Cord Injuries / Q000235:genetics / Q000473:pathology
chemical_list: D011508:Chondroitin Sulfate Proteoglycans