June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Intranasal delivery of mesenchymal secretome prevents traumatic brain injury-induced disease-associated microglia to protect visual function
Author Affiliations & Notes
  • Rajashekhar Gangaraju
    Ophthalmology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
    Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Pratheepa Rasiah
    Ophthalmology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Mohd Salman
    Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Saifudeen Ismael
    Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Sally Elshaer
    Ophthalmology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Tauheed Ishrat
    Anatomy & Neurobiology, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Mickey Pentecost
    Diadem Biotherapeutics, Inc, Los Angeles, California, United States
  • Footnotes
    Commercial Relationships   Rajashekhar Gangaraju Cell Care Therapeutics, Inc, Code I (Personal Financial Interest); Pratheepa Rasiah None; Mohd Salman None; Saifudeen Ismael None; Sally Elshaer None; Tauheed Ishrat None; Mickey Pentecost Diadem Biotherapeutics, Inc, Code O (Owner), Diadem Biotherapeutics, Inc, Code P (Patent)
  • Footnotes
    Support  NH Grant R56 NS127924-01
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3859. doi:
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    • Get Citation

      Rajashekhar Gangaraju, Pratheepa Rasiah, Mohd Salman, Saifudeen Ismael, Sally Elshaer, Tauheed Ishrat, Mickey Pentecost; Intranasal delivery of mesenchymal secretome prevents traumatic brain injury-induced disease-associated microglia to protect visual function. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3859.

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

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Abstract

Purpose : We have demonstrated that intravitreal injection of human adipose stem cell concentrated conditioned media containing exosomes (ASC-CCM) is safe and effective against visual deficits of TBI. This study aims to develop a non-invasive route of ASC-CCM delivery to reduce disease-associated microglia (DAM) state post-TBI.

Methods : Adult male C57BL/6J or Cx3cr1 mice were subjected to controlled cortical impact (CCI) TBI. ASC-CCM (with or without fluorescent labeling of exosomes) was administered via the intranasal route (4x, ~20ng protein/day). As controls, TBI only and Sham mice received saline. After 4 weeks of treatment, visual function was assessed by ERG and OKN, differential expression by qRT-PCR, and tissue expression of DAM by immunohistology. In vitro, the efficacy of ASC-CCM to decrease phagocytosis of FluoroSpheres due to APOE overexpression was assessed in cultured BV2 microglia.

Results : Fluorescently labeled exosomes within ASC-CCM were detected near optic nerve. Compared to Sham mice, TBI mice that received saline showed lower visual acuity (0.27±0.02 vs. 0.37±0.0, c/d, p<0.001) and a higher requirement for contrast (74±7 vs. 14±3.4, c/d, p<0.001) to discriminate 0.042 cycles/degree and lower b-wave amplitudes (401.8±19 vs. 450.4±27.5, μV, p<0.05) in the scotopic ERG. On the other hand, TBI mice receiving ASC-CCM significantly improved all the above (p<0.001, p<0.001, p<0.01, respectively; n= 4-5/group). Increased Müller GFAP and loss of RGC (βIII-Tubulin) correlated with increased APOE in Müller cells and TYROBP in Cx3cr1 microglia, which was reduced in animals receiving ASC-CCM. DEGs showed upregulation of genes associated with DAM state (TREM2, TYROBP, APOE, CD68, CD86, IL1β) in the retina of TBI mice receiving saline with a significant improvement in 5 out of 6 gene transcripts in TBI mice receiving ASC-CCM (p<0.05; n=4-5/group). Overexpression of APOE or LPS/IFNγ increased phagocytosis in BV2 microglia, which could be suppressed with ASC-CCM (p<0.001).

Conclusions : This is the first observation that the mesenchymal secretome benefits vision in TBI via a non-invasive route. Although more studies are warranted, mesenchymal stem cell therapies will likely help preserve vision in TBI via their regulation of DAM state to homeostatic microglia.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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