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A new immunodeficient retinal dystrophic rat model for transplantation studies using human-derived cells

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Abstract

Purpose

To create new immunodeficient Royal College of Surgeons (RCS) rats by introducing the defective MerTK gene into athymic nude rats.

Methods

Female homozygous RCS (RCS-p+/RCS-p+) and male nude rats (Hsd:RH-Foxn1mu, mutation in the foxn1 gene; no T cells) were crossed to produce heterozygous F1 progeny. Double homozygous F2 progeny obtained by crossing the F1 heterozygotes was identified phenotypically (hair loss) and genotypically (RCS-p+ gene determined by PCR). Retinal degenerative status was confirmed by optical coherence tomography (OCT) imaging, electroretinography (ERG), optokinetic (OKN) testing, superior colliculus (SC) electrophysiology, and by histology. The effect of xenografts was assessed by transplantation of human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) and human-induced pluripotent stem cell-derived RPE (iPS-RPE) into the eye. Morphological analysis was conducted based on hematoxylin and eosin (H&E) and immunostaining. Age-matched pigmented athymic nude rats were used as control.

Results

Approximately 6% of the F2 pups (11/172) were homozygous for RCS-p+ gene and Foxn1mu gene. Homozygous males crossed with heterozygous females resulted in 50% homozygous progeny for experimentation. OCT imaging demonstrated significant loss of retinal thickness in homozygous rats. H&E staining showed photoreceptor thickness reduced to 1–3 layers at 12 weeks of age. Progressive loss of visual function was evidenced by OKN testing, ERG, and SC electrophysiology. Transplantation experiments demonstrated survival of human-derived cells and absence of apparent immune rejection.

Conclusions

This new rat animal model developed by crossing RCS rats and athymic nude rats is suitable for conducting retinal transplantation experiments involving xenografts.

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Acknowledgements

This study was supported by CIRM TR4-06648 (MJS), CIRM DT3 (MSH), Bright Focus Foundation (BBT), and Research to Prevent Blindness (USC Roski Eye Institute). We want to thank Dr. Kapil Bharti (National Institute of Health, Bethesda, MD, USA) for providing the iPS-RPE, Xiaopeng Wang (USC), and Bryce McLelland, Anuradha Mathur, Jessica Quynh Huong Duong, Marissa Mahtob Marie Monazzami, and Luxi Zhang (UC Irvine) for technical assistance.

Funding

Supported by CIRM (MJS, MSH, DRH), Bright Focus Foundation (BBT), and Research to Prevent Blindness (USC Roski Eye Institute). The sponsor had no role in the design or conduct of this research.

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Authors and Affiliations

  1. Department of Ophthalmology, USC Roski Eye Institute, University of Southern California, Los Angeles, CA, 90033, USA

    Biju B. Thomas, Danhong Zhu, Tai-Chi Lin, Young Chang Kim, Juan Carlos Martinez-Camarillo, David R. Hinton & Mark S. Humayun

  2. USC Institute for Biomedical Therapeutics, University of Southern California, Los Angeles, CA, USA

    Biju B. Thomas, Tai-Chi Lin, Juan Carlos Martinez-Camarillo & Mark S. Humayun

  3. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Danhong Zhu, Young Chang Kim & David R. Hinton

  4. Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China

    Tai-Chi Lin

  5. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China

    Tai-Chi Lin

  6. Department of Physical Medicine & Rehabilitation, University of California-Irvine, Irvine, CA, USA

    Magdalene J. Seiler & Bin Lin

  7. Stem Cell Research Center, University of California-Irvine, Irvine, CA, USA

    Magdalene J. Seiler & Bin Lin

  8. Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada

    Yousuf Shad

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  1. Biju B. Thomas
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Correspondence to Biju B. Thomas.

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Conflict of interest

MJS has proprietary interest in the instrument and method for transplanting retinal sheets (Ocular Transplantation LLC). MSH and DRH are co-founders and consultants to Regenerative Patch Technologies (RPT). The other authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements) or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of the animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of University of Southern California Institutional Animal Care and Use Committee (IACUC).

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Thomas, B.B., Zhu, D., Lin, TC. et al. A new immunodeficient retinal dystrophic rat model for transplantation studies using human-derived cells. Graefes Arch Clin Exp Ophthalmol 256, 2113–2125 (2018). https://doi.org/10.1007/s00417-018-4134-2

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