Interleukin-13 Gene Modification Enhances Grafted Mesenchymal Stem Cells Survival After Subretinal Transplantation

Abstract

Mesenchymal stem cells (MSCs) hold great potential for cell- and gene-based therapies for retinal degeneration. Limited survival is the main obstacle in achieving successful subretinal transplantation of MSCs. The present study sought to evaluate the effect of interleukin-13 (IL-13) gene modification on the phenotypic alteration of retinal microglia (RMG) and the survival of MSCs following subretinal grafting. In this study, LPS-activated RMG were cocultured with MSCs or IL-13-expressing MSCs (IL-13-MSCs) for 24 h, and activated phenotypes were detected in vitro. Western blotting was performed to quantify cytokine secretion by light-injured retinas following subretinal transplantation. The numbers of activated RMG and surviving grafted cells were analysed, and the integrity of the blood–retinal barrier (BRB) was examined in vivo. We found that, compared with normal MSCs, cocultured IL-13-MSCs suppressed the expression of pro-inflammatory factors and major histocompatibility complex II, promoted the expression of anti-inflammatory cytokines by activated RMG and simultaneously inhibited the proliferation of and phagocytosis by RMG. The subretinal transplantation of IL-13-MSCs increased the expression of neurotrophic factors, IL-13 and tight junction proteins in the host retina, decreased the number of phagocytic RMG and improved the survival of grafted cells. Furthermore, IL-13-MSCs alleviated BRB breakdown induced by subretinal injection. Our results demonstrate that IL-13-MSCs can polarize activated RMG to the neuroprotective M2 phenotype and enhance the survival of grafted MSCs against the damage stress induced by subretinal transplantation.

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Abbreviations

MSCs:

Mesenchymal stem cells

MHC:

Major histocompatibility complex

BRB:

Blood–retinal barrier

RMG:

Retinal microglia

IL-13:

Interleukin-13

IL-13-MSCs:

Interleukin-13 gene-modified mesenchymal stem cells

LV:

Lentivirus

LPS:

Lipopolysaccharides

RPE:

Retinal pigment epithelium

TNF-α:

Tumour necrosis factor-α

IL-1β:

Interleukin-1β

IL-10:

Interleukin-10

CNTF:

Ciliary neurotrophic factor

GDNF:

Glial cell-derived neurotrophic factor

ZO-1:

Zonula occludens-1

SEM:

Scanning electron microscopy

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Funding

This study was supported by grants from Startup Fund for scientific research of Fujian Medical University (Grant Number: 2016QH041), and Fund for Young and Middle-aged University Teachers’ educational research of Fujian Province (Grant Number: JT180188).

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Authors

Contributions

HL performed and analysed majority of all experiments, including cell coculture and subretinal transplantation. XM and YJ participated in most of the experiments. HL and YY conceived and designed the experiments. The manuscript was written by HL, XM and YJ. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Maosong Xie.

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The authors declare that they have no competing interests.

Ethical Approval

All animal procedures were approved by the Animal Care and Use Committee of the First Affiliated Hospital of Fujian Medical University (no.2016-YK-163) and conformed to the Association for Research in Vision and Ophthalmology (ARVO) Statement on the Use of Animals in Ophthalmic and Vision Research. All efforts were resorted to minimize the number of rats used and their suffering.

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Cite this article

Huang, L., You, J., Yao, Y. et al. Interleukin-13 Gene Modification Enhances Grafted Mesenchymal Stem Cells Survival After Subretinal Transplantation. Cell Mol Neurobiol 40, 725–735 (2020). https://doi.org/10.1007/s10571-019-00768-3

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Keywords

  • Mesenchymal stem cell
  • Microglia
  • Graft survival
  • Interleukin-13
  • Subretinal transplantation
  • Blood–retinal barrier