June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Neurotrauma induced retinal basement membrane Col4a1 defects are restored by Adipose tissue derived mesenchymal stem cell concentrated conditioned medium
Author Affiliations & Notes
  • Pratheepa Rasiah
    Ophthalmology, The University of Tennessee Health Science Center College of Medicine, Memphis, Tennessee, United States
  • Kumar Abhiram Jha
    Ophthalmology, The University of Tennessee Health Science Center College of Medicine, Memphis, Tennessee, United States
  • Jordy Gentry
    Ophthalmology, The University of Tennessee Health Science Center College of Medicine, Memphis, Tennessee, United States
  • Nobel Del Mar
    Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Anton Reiner
    Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Rajashekhar Gangaraju
    Ophthalmology, The University of Tennessee Health Science Center College of Medicine, Memphis, Tennessee, United States
    Anatomy and Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Footnotes
    Commercial Relationships   Pratheepa Rasiah, None; Kumar Abhiram Jha, None; Jordy Gentry, None; Nobel Del Mar, None; Anton Reiner, None; Rajashekhar Gangaraju, Cell Care Therapeutics Inc (I), Cell Care Therapeutics Inc (P)
  • Footnotes
    Support  Department of Defense (W81XWH-16-1-0761)
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1360. doi:
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      Pratheepa Rasiah, Kumar Abhiram Jha, Jordy Gentry, Nobel Del Mar, Anton Reiner, Rajashekhar Gangaraju; Neurotrauma induced retinal basement membrane Col4a1 defects are restored by Adipose tissue derived mesenchymal stem cell concentrated conditioned medium. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1360.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : The goal of our study was to determine if Col4a1 deficiency exacerbates the visual deficits after mild traumatic brain injury (mTBI), and demonstrate the efficacy of COL4A1 enriched ASC concentrated conditioned medium (ASC-CCM) in restoring retinal vascular health after mTBI and mitigating visual deficits

Methods : Two-month-old C57Bl/6 mice were subjected to retina-specific knockdown of Col4a1 with intravitreally delivered AAV2-Col4shRNA and later to a 50-psi air pulse to the left side of the head, resulting in an mTBI, and compared to Control-shRNA treated mice with mTBI. Post blast, ASC-CCM (~100ng/eye/1mL) was delivered intravitreally, followed by visual assessment, immunohistology, and gene expression analysis after 4 weeks. Immune depletion of COL4A1 from ASC condition media was evaluated for the role of COL4A1 in the anti-inflammatory effects of ASC-CCM on microglial activation and endothelial permeability in vitro. Human retinal endothelial cells (HREC) with knockdown of Col4a1 via siRNA transfection were assessed for endothelial migration and leukocyte transmigration with COL4A1-enriched ASC-CCM

Results : mTBI resulted in a significant reduction in visual acuity and contrast sensitivity in mice, worsen with Col4a1 knockdown (p<0.001). An intravitreal injection of ASC-CCM rescued visual function in mTBI mice with Col4a1 knockdown (p<0.05). Immunohistological and gene expression analysis of retinas of mTBI mice with Col4a1 knockdown demonstrated increased gene transcripts indicative of glial and endothelial activation (p<0.05) and retinal vascular and synaptic junction defects, which were significantly improved in blast mice with Col4a1 knockdown receiving ASC-CCM. COL4A1-enriched but not COL4A1-immunodepleted ASC-CCM prevented cytokine stimulated microglial nitrite release as well as TNF-α induced endothelial permeability in vitro. HRECs with knockdown of Col4a1 (~90%) mimicked known pathogenic vascular defects, exhibiting impaired HREC migration and increased transmigration of leukocytes, which was remedied by COL4A1 enriched ASC-CCM (p<0.05)

Conclusions : Our studies demonstrate that pre-existing Col4a1 deficiency can exacerbate the TBI outcome and thus be a TBI risk factor in humans. Additionally, our studies confirm the efficacy of ASC-CCM administration in treating Col4a1 deficiency in neurotrauma

This is a 2021 ARVO Annual Meeting abstract.

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