RT Journal Article
SR Electronic
T1 Human photoreceptor cell transplants integrate into human retina organoids
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.09.500037
DO 10.1101/2022.08.09.500037
A1 Felix Wagner
A1 Roberto Carrera
A1 Thomas Kurth
A1 Stylianos Michalakis
A1 Ronald Naumann
A1 Marta Zuzic
A1 Katrin Neumann
A1 Olivier Gourau
A1 Volker Busskamp
A1 Mike O. Karl
YR 2022
UL http://biorxiv.org/content/early/2022/08/11/2022.08.09.500037.abstract
AB Cell transplantation is a promising therapeutic approach to recover loss of neurons and vision in patient retinas. So far, human photoreceptor transplants restored some visual function in degenerating mouse retina. Whether retinal cell transplants also integrate into human retina, and how to optimize this for different pathologies are still unknown. Here, we sought to determine if human retina organoids generated from pluripotent stem cells might assist cell replacement therapy development in a human-to-human setting. Models for intra- and subretinal cell transplantation strategies were explored: Photoreceptor donor cells carrying a transgenic fluorescent reporter were enriched from acutely dissociated human retinal organoids. Donor cells were precisely transplanted by microinjection into the retina of host organoids, but high cell numbers might require multiple injections posing potential damage. Alternatively, donor cells were transplanted in large numbers by placing them in subretinal-like contact to the apical organoid surface. Using postmitotic retinal organoids (age >170-days) as a source for donor cells and as hosts, we show that six weeks after subretinal-like transplantation, large clusters of photoreceptors reproducibly incorporate into the host retina. Transplanted clusters frequently are located within or across the host photoreceptor layer, include cone and rod photoreceptors, and become infiltrated by cell processes of host Müller glia, indicative of structural integration. Histological and ultrastructural data of virally-labeled photoreceptor transplants show characteristic morphological and structural features of polarized photoreceptors: inner segments and ribbon synapses, and donor-host cell contacts develop contributing to the retinal outer limiting membrane. These results demonstrate that human retinal organoids provide a preclinical research system for cell replacement therapies.Competing Interest StatementOG is inventor on patents on hiPSC retinal differentiation (patent nos. EP2989200/WO2018149985) and on the use of hiPSC retinal derivatives to treat retinal degeneration (patent no. WO2018055131), licensed to Gamut Cell Tx. All other authors declare no competing interests.