June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
HiPSC-derived cones incorporate, mature and survive long-term in a mouse model of cone-degeneration
Author Affiliations & Notes
  • Sylvia Jane Gasparini
    TU-Dresden, CRTD - Centre for Regenerative Therapies Dresden, Dresden, Saxony, Germany
  • Karen Tessmer
    TU-Dresden, CRTD - Centre for Regenerative Therapies Dresden, Dresden, Saxony, Germany
  • Madalena Carido
    TU-Dresden, CRTD - Centre for Regenerative Therapies Dresden, Dresden, Saxony, Germany
    DZNE - German Center for Neurodegenerative Diseases, Dresden, Dresden, Saxony, Germany
  • Oliver Borsch
    TU-Dresden, CRTD - Centre for Regenerative Therapies Dresden, Dresden, Saxony, Germany
  • Stephanie Wieneke
    DZNE - German Center for Neurodegenerative Diseases, Dresden, Dresden, Saxony, Germany
  • Anka Kempe
    TU-Dresden, CRTD - Centre for Regenerative Therapies Dresden, Dresden, Saxony, Germany
  • Marta Zusic
    Ophthalmology, University of Bonn, Bonn, Nordrhein-Westfalen, Germany
  • Manuela Völkner
    DZNE - German Center for Neurodegenerative Diseases, Dresden, Dresden, Saxony, Germany
  • Mike O Karl
    TU-Dresden, CRTD - Centre for Regenerative Therapies Dresden, Dresden, Saxony, Germany
    DZNE - German Center for Neurodegenerative Diseases, Dresden, Dresden, Saxony, Germany
  • Volker Busskamp
    Ophthalmology, University of Bonn, Bonn, Nordrhein-Westfalen, Germany
  • Marius Ader
    TU-Dresden, CRTD - Centre for Regenerative Therapies Dresden, Dresden, Saxony, Germany
  • Footnotes
    Commercial Relationships   Sylvia Gasparini, None; Karen Tessmer, None; Madalena Carido, None; Oliver Borsch, None; Stephanie Wieneke, None; Anka Kempe, None; Marta Zusic, None; Manuela Völkner, None; Mike Karl, None; Volker Busskamp, None; Marius Ader, None
  • Footnotes
    Support  BMBF consortium 'ReSight'
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 3305. doi:
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      Sylvia Jane Gasparini, Karen Tessmer, Madalena Carido, Oliver Borsch, Stephanie Wieneke, Anka Kempe, Marta Zusic, Manuela Völkner, Mike O Karl, Volker Busskamp, Marius Ader; HiPSC-derived cones incorporate, mature and survive long-term in a mouse model of cone-degeneration. Invest. Ophthalmol. Vis. Sci. 2021;62(8):3305.

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

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Abstract

Purpose : Humans rely on high acuity and daylight vision – both of which are mediated by cone photoreceptors. Once photoreceptors die, they do not regenerate. Thus cell transplantation has emerged as a treatment strategy. While retinal organoids hold promise as an unlimited cell source, human cone transplantations have so far been hampered by a lack of efficient cone cell enrichment by surface markers. In this study a cone specific GFP-reporter hiPSC line was generated, facilitating this cone transplantation study.

Methods : A mArr3-GFP hiPSC line was utilized in an optimized protocol to produce robust numbers of cones (up to 45%) in retinal organoids. FAC-sorted cones of day 200 organoids were transplanted into cone photoreceptor function loss 1 mice (Cpfl1) which exhibit rapid cone loss. Using local immune suppression, the transplants survived well, allowing long term follow up at 3, 10 and 26 weeks (wk). Transplants were examined via immunohistochemistry, electron microscopy and RNA sequencing.

Results : At 3wks the human cones remained largely in the subretinal space, but, by 10wks a bulk migration of the graft into the host outer nuclear layer was observed, a behavior which has not been described previously. Transplanted cones appeared to be well tolerated by the mouse retina – rather than forming a glial barrier, Müller Glia cells enveloped the graft. In addition, bipolar and horizontal cells extend processes to the human cones, a requisite for synaptic connectivity. Transplanted cones continued to mature in vivo, where by 10wks, some cones developed characteristic photoreceptor features of ribbon synapses and inner segments. By 26wks the human cones further matured, developing outer segment structures. Of note, only cones interacting with the host retina developed these features, while cones within the subretinal space lacked signs of maturation. Remarkably, the xenogeneic environment did not negatively alter maturation of the human cones, as evidenced by the high degree of similarity between the RNA expression profiles of in vivo vs in vitro matured cones, as well as to primary fetal human cones.

Conclusions : Overall these results indicate that human cones are well tolerated, mature normally and interact readily with the dystrophic mouse retina. This is an important achievement in photoreceptor transplantation research and opens up possibilities for further research towards clinical application.

This is a 2021 ARVO Annual Meeting abstract.

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