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Potential neuroprotective effect of stem cells from apical papilla derived extracellular vesicles enriched by lab-on-chip approach during retinal degeneration

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Abstract

Retinal degeneration (RD) is recognized as a frequent cause of visual impairments, including inherited (Retinitis pigmentosa) and degenerative (age-related macular) eye diseases. Dental stem cells (DSCs) have recently demonstrated a promising neuroprotection potential for ocular diseases through a paracrine manner carried out by extracellular vesicles (EVs). However, effective isolation of EVs is still challenging, and isolation methods determine the composition of enriched EVs and the subsequent biological and functional effects. In the present study, we assessed two enrichment methods (micro-electromechanical systems and ultrafiltration) to isolate the EVs from stem cells from apical papilla (SCAP). The size distribution of the corresponding isolates exhibited the capability of each method to enrich different subsets of EVs, which significantly impacts their biological and functional effects. We confirmed the neuroprotection and anti-inflammatory capacity of the SCAP-EVs in vitro. Further experiments revealed the possible therapeutic effects of subretinal injection of SCAP-EVs in the Royal College of Surgeons (RCS) rat model. We found that EVs enriched by the micro-electromechanical-based device (MEMS-EVs) preserved visual function, reduced retinal cell apoptosis, and prevented thinning of the outer nuclear layer (ONL). Interestingly, the effect of MEMS-EVs was extended to the retinal ganglion cell/retinal nerve fiber layer (GCL/RNFL). This study supports the use of the microfluidics approach to enrich valuable subsets of EVs, together with the choice of SCAP as a source to derive EVs for cell-free therapy of RD.

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Fig. 1

source to derive EVs. a Bright-field (phase contrast) image of homogenous spindle-shaped SCAP, b Electron micrograph of SCAP ultrastructure; arrows show MVB containing EVs, c sEVs: small (30–110 nm), d m/lEVs: medium to large (100–1000 nm) (yellow arrow), e Experimental workflow of conditioned medium collection, f Electron micrograph of conditioned medium indicating a heterogeneous population of EVs (yellow arrow), g Flow cytometry analysis; the area under the pink line identifies EVs reacting with CD81. The area under the yellow line indicates the interactions of EVs with corresponding non-reactive immunoglobulin of the same isotype. h Western blot results of SCAP conditioned medium. SCAP stem cells from apical papilla, EV extracellular vesicles, MVB multivesicular bodies, CM conditioned medium

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Acknowledgements

The authors wish to express their gratitude to Professor Hossein Baharvand and Dr. Faezeh Shekari for providing rhodopsin antibody and excellent technical assistance.

Funding

This study is based upon work supported by the Irans’ National Elites Foundation (INEF).

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Authors and Affiliations

  1. Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran

    Hanieh Hadady, Fereshteh Karamali, Fatemeh Ejeian, Sareh Soroushzadeh & Mohammad Hossein Nasr-Esfahani

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  1. Hanieh Hadady
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Correspondence to Fereshteh Karamali or Mohammad Hossein Nasr-Esfahani.

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Animal care and experimental procedures were performed in accordance with the Helsinki Declaration and compiled with the ARRIVE guideline (https://arriveguidelines.org/) and were approved by the institutional research ethics committee at Royan institute (IR.ACECR.ROYAN.REC.1400.043).

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Hadady, H., Karamali, F., Ejeian, F. et al. Potential neuroprotective effect of stem cells from apical papilla derived extracellular vesicles enriched by lab-on-chip approach during retinal degeneration. Cell. Mol. Life Sci. 79, 350 (2022). https://doi.org/10.1007/s00018-022-04375-2

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