PMID- 29959434 OWN - NLM STAT- MEDLINE DCOM- 20191024 LR - 20240328 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 8 IP - 1 DP - 2018 Jun 29 TI - The extent of extra-axonal tissue damage determines the levels of CSPG upregulation and the success of experimental axon regeneration in the CNS. PG - 9839 LID - 10.1038/s41598-018-28209-z [doi] LID - 9839 AB - The failure of mature central nervous system (CNS) projection neurons to regenerate axons over long distances drastically limits the recovery of functions lost after various CNS injuries and diseases. Although a number of manipulations that stimulate some degree of axon regeneration that overcomes the inhibitory environment after CNS injury have been discovered, the extent of regeneration remains very limited, emphasizing the need for improved therapies. Regenerating axons need nerve tissue environment capable of supporting their growth, and severe extra-axonal tissue damage and remodeling after injury may disrupt such environment. Here, we used traumatic injury to the mouse optic nerve as a model system to investigate how the extent of extra-axonal tissue damage affects experimental axon regeneration. Axon regeneration was stimulated by the shRNA-mediated knockdown (KD) of Pten gene expression in the retinal ganglion cells, and the extent of extra-axonal tissue damage was varied by changing the duration of optic nerve crush. Although no axons were spared using either 1 or 5 seconds crush, we found that Pten KD-stimulated axon regeneration was significantly reduced in 5 seconds compared with 1 second crush. The more severe extra-axonal tissue damage did not cause tissue atrophy, but led to significantly higher upregulation of axon growth-inhibiting chondroitin sulfate proteoglycan (CSPG) in the glial scar and also enlarged glial scar size, compared with less severely damaged tissue. Thus, the success of axon-regenerating approaches that target neuronal intrinsic mechanisms of axon growth is dependent on the preservation of appropriate extra-axonal tissue environment, which may need to be co-concurrently repaired by tissue remodeling methods. FAU - Kim, Juhwan AU - Kim J AD - Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT, 06030, USA. FAU - Sajid, Muhammad S AU - Sajid MS AD - Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT, 06030, USA. AD - University of Hartford, 200 Bloomfield Ave., West Hartford, CT, 06117, USA. FAU - Trakhtenberg, Ephraim F AU - Trakhtenberg EF AUID- ORCID: 0000-0003-2844-4191 AD - Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT, 06030, USA. trakhtenberg@uchc.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180629 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Chondroitin Sulfate Proteoglycans) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (Pten protein, mouse) SB - IM MH - Animals MH - Axons/*physiology MH - Central Nervous System/cytology/*physiology MH - Chondroitin Sulfate Proteoglycans/administration & dosage/genetics/*metabolism MH - Male MH - Mice MH - *Nerve Regeneration MH - Neuroglia/*pathology MH - PTEN Phosphohydrolase/antagonists & inhibitors/genetics/*metabolism MH - Retinal Ganglion Cells/*cytology/physiology MH - Up-Regulation PMC - PMC6026156 COIS- The authors declare no competing interests. EDAT- 2018/07/01 06:00 MHDA- 2019/10/28 06:00 PMCR- 2018/06/29 CRDT- 2018/07/01 06:00 PHST- 2018/04/17 00:00 [received] PHST- 2018/06/19 00:00 [accepted] PHST- 2018/07/01 06:00 [entrez] PHST- 2018/07/01 06:00 [pubmed] PHST- 2019/10/28 06:00 [medline] PHST- 2018/06/29 00:00 [pmc-release] AID - 10.1038/s41598-018-28209-z [pii] AID - 28209 [pii] AID - 10.1038/s41598-018-28209-z [doi] PST - epublish SO - Sci Rep. 2018 Jun 29;8(1):9839. doi: 10.1038/s41598-018-28209-z.