PMID- 32387619
OWN - NLM
STAT- MEDLINE
DCOM- 20210108
LR  - 20210108
IS  - 1096-0007 (Electronic)
IS  - 0014-4835 (Linking)
VI  - 196
DP  - 2020 Jul
TI  - Leucine-rich alpha-2-glycoprotein-1 promotes diabetic corneal epithelial wound 
      healing and nerve regeneration via regulation of matrix metalloproteinases.
PG  - 108060
LID - S0014-4835(20)30319-5 [pii]
LID - 10.1016/j.exer.2020.108060 [doi]
AB  - Leucine-rich alpha-2-glycoprotein-1 (LRG1) is involved in several pathophysiological 
      processes, including angiogenesis, cutaneous wound repair and cancer metastasis. 
      In this study, we investigated the potential role and mechanism of LRG1 in 
      corneal re-epithelialisation and nerve regeneration in streptozotocin-induced 
      diabetic mice. We found decreased levels of LRG1 in the corneal epithelium after 
      wounding in diabetic mice compared to normal controls. Hyperglycaemia 
      downregulated the LRG1 expression in the corneal epithelium in vivo, as well as 
      in vitro in a cultured mouse corneal epithelial stem/progenitor cell line (TKE2 
      cells) exposed to high glucose (HG; 30 mM) in the culture medium. Exogenous 
      application of LRG1 accelerated corneal re-epithelialisation and nerve 
      regeneration in normal mice and diabetic mice. LRG1 also overcame the suppression 
      of wound healing in TKE2 cells by HG conditions, and it activated repair-related 
      signalling by JAK2/STAT3, AKT, epidermal growth factor receptor (EGFR) and 
      transforming growth factor (TGF)-beta3. We also found that LRG1 treatment overcame 
      the hyperglycaemia-suppressed expression of matrix metalloproteinase 3 (MMP3) and 
      metalloproteinase 13 (MMP13) in the regenerated corneal epithelium. The promoted 
      effects of LRG1 on corneal re-epithelialisation and nerve regeneration were 
      blocked by inhibitors of MMP3 and MMP13. Subconjunctival injection of 0.5 mug MMP 
      inhibitors did not cause any obvious toxic damage in corneal epithelial cells. 
      Immunoprecipitation and proximity ligation assay experiments confirmed that 
      endogenous LRG1 coprecipitated with MMP3 and MMP13 in TKE2 cells. These results 
      indicate that LRG1 promoted wound repair and nerve regeneration in the diabetic 
      corneal epithelium by regulation of MMPs. Our findings reveal a new function and 
      mechanism for LRG1 in the cornea, and they provide new insights for a better 
      understanding of diabetic keratopathy.
CI  - Copyright (c) 2020 Elsevier Ltd. All rights reserved.
FAU - Li, Weina
AU  - Li W
AD  - Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430060, 
      China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory 
      of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China.
FAU - Wang, Xiaochuan
AU  - Wang X
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China; School of Medicine 
      and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, 
      Jinan, 250002, China.
FAU - Cheng, Jun
AU  - Cheng J
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China.
FAU - Li, Jing
AU  - Li J
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China; School of Medicine 
      and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, 
      Jinan, 250002, China.
FAU - Wang, Qun
AU  - Wang Q
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China.
FAU - Zhou, Qingjun
AU  - Zhou Q
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China.
FAU - Li, Hua
AU  - Li H
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China.
FAU - Xue, Junfa
AU  - Xue J
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China.
FAU - Zhang, Yuan
AU  - Zhang Y
AD  - Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430060, 
      China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory 
      of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China.
FAU - Yang, Lingling
AU  - Yang L
AD  - State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of 
      Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China. Electronic address: 
      lingling6008@126.com.
FAU - Xie, Lixin
AU  - Xie L
AD  - Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430060, 
      China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory 
      of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & 
      Shandong Academy of Medical Sciences, Qingdao, 266071, China. Electronic address: 
      lixin_xie@hotmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200506
PL  - England
TA  - Exp Eye Res
JT  - Experimental eye research
JID - 0370707
RN  - 0 (Glycoproteins)
RN  - 0 (LRG1 protein, mouse)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (Stat3 protein, mouse)
RN  - 0 (Transforming Growth Factor beta3)
RN  - EC 2.7.10.1 (EGFR protein, mouse)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.2 (Jak2 protein, mouse)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Cornea/innervation/metabolism
MH  - Corneal Diseases/*metabolism
MH  - Diabetes Mellitus, Experimental/metabolism
MH  - Diabetes Mellitus, Type 1/metabolism
MH  - Epithelium, Corneal/*physiology
MH  - ErbB Receptors/metabolism
MH  - Glucose/pharmacology
MH  - Glycoproteins/*physiology
MH  - Hyperglycemia/metabolism
MH  - Janus Kinase 2/metabolism
MH  - Male
MH  - Matrix Metalloproteinases/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nerve Regeneration/*physiology
MH  - Oncogene Protein v-akt/metabolism
MH  - Re-Epithelialization
MH  - STAT3 Transcription Factor/metabolism
MH  - Transforming Growth Factor beta3/metabolism
MH  - Trigeminal Nerve/*physiology
MH  - Wound Healing/*physiology
OTO - NOTNLM
OT  - Corneal epithelial wound healing
OT  - Diabetic
OT  - Leucine-rich alpha-2-glycoprotein-1
OT  - Matrix metalloproteinases
OT  - Nerve regeneration
COIS- Declaration of competing interest All authors have approved this final article as 
      being true in representation of the experimental findings.
EDAT- 2020/05/11 06:00
MHDA- 2021/01/09 06:00
CRDT- 2020/05/11 06:00
PHST- 2019/10/17 00:00 [received]
PHST- 2020/04/23 00:00 [revised]
PHST- 2020/04/28 00:00 [accepted]
PHST- 2020/05/11 06:00 [pubmed]
PHST- 2021/01/09 06:00 [medline]
PHST- 2020/05/11 06:00 [entrez]
AID - S0014-4835(20)30319-5 [pii]
AID - 10.1016/j.exer.2020.108060 [doi]
PST - ppublish
SO  - Exp Eye Res. 2020 Jul;196:108060. doi: 10.1016/j.exer.2020.108060. Epub 2020 May 
      6.