June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Preclinical human model for retinal cell therapy: Pathology dependent integration of photoreceptor transplants into human retina organoid hosts
Author Affiliations & Notes
  • Felix Wagner
    Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, Dresden, Germany
    German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
  • Roberto Carrera
    German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
  • Thomas Kurth
    Technical University Dresden, Center for Molecular and Cellular Bioengineering (CMCB), Technology Platform, Core Facility Electron Microscopy and Histology, Dresden, Germany
  • Stylianos Michalakis
    Department of Ophthalmology, University Hospital, LMU Munich, Munich, Germany
  • Deniz Dalkara
    Sorbonne Université, Institut de la Vision, Paris, France
  • Mike O. Karl
    Center for Regenerative Therapies Dresden (CRTD), Technical University Dresden, Dresden, Germany
    German Center for Neurodegenerative Diseases (DZNE), Dresden, Germany
  • Footnotes
    Commercial Relationships   Felix Wagner None; Roberto Carrera None; Thomas Kurth None; Stylianos Michalakis ViGeneron GmbH, Code O (Owner); Deniz Dalkara None; Mike Karl None
  • Footnotes
    Support  DFG SPP2127, BMBF ReDiMoAMD
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3858. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Felix Wagner, Roberto Carrera, Thomas Kurth, Stylianos Michalakis, Deniz Dalkara, Mike O. Karl; Preclinical human model for retinal cell therapy: Pathology dependent integration of photoreceptor transplants into human retina organoid hosts. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3858.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : Cell transplantation is a promising future therapy to prevent and restore loss of neurons and vision in retinal diseases. Transplanted mouse photoreceptors – unlike human – rarely integrate into mouse retina but exchange cellular material with host cells. We hypothesized that retina organoids allow to study cell replacement therapy in a preclinical human setting. A key question for clinical translation is: Can human photoreceptors integrate into human retina, and which pathology type and stage would be optimal?

Methods : We used human retina organoids at postmitotic stage (day 200) to develop an in vivo-like cell transplantation system: Human photoreceptors were isolated from CRX-mCHERRY nuclear reporter organoids and transplanted onto host human retina organoids (without reporter). Hosts with or without photoreceptor degeneration, experimentally induced by HBEGF-TNF treatment, were used – former at intermediate and late pathology stages. Analyses included live-imaging, histology, and viral tracing of donor cells with cone-specific reporters.

Results : Rod and cone photoreceptor transplants placed in subretinal-like contact with healthy hosts spontaneously incorporated as large cell clusters after six weeks. Material transfer of fluorophores was not evident, as evaluated by a dual-reporter approach. (Ultra)structural studies showed characteristic morphological features of photoreceptor transplants indicating structural integration into the host retina. Transplant incorporation frequency was comparably high in healthy and pathologic hosts (mean ± standard deviation: 74±21%, n=72, N=3). Interestingly, at late pathology stages with extensive glial scarring, transplants still incorporated but with a different phenotype: photoreceptors incorporated as single cells scattered across the host retina instead of one large cell cluster.

Conclusions : We established a preclinical human system for retina cell replacement therapy and observed for the first time human photoreceptor transplant integration into a human retina model. Our data indicate that the pathology stage might influence cell transplantation outcome. Thus, this human transplantation system might assist mechanistic studies, preclinical optimization, and clinical translation of cell replacement therapy for various cell types and diseases.

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

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×