Transplanted human cones incorporate into the retina and function in a murine cone degeneration model

Research output: Contribution to journalResearch articleContributedpeer-review

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Abstract

Once human photoreceptors die, they do not regenerate, thus photoreceptor transplantation has emerged as a potential treatment approach for blinding diseases. Improvements in transplant organization, donor cell maturation and synaptic connectivity to the host will be critical in advancing this technology to clinical practice. Unlike the unstructured grafts of prior cell suspension transplantations into end-stage degeneration models, we describe extensive incorporation of iPSC retinal organoid-derived human photoreceptors into mice with cone dysfunction. This incorporative phenotype was validated in both cone-only as well as pan-photoreceptor transplantations. Rather than forming a glial barrier, Müller cells extended throughout the graft, even forming a series of adherens junctions between mouse and human cells, reminiscent of an outer limiting membrane. Donor-host interaction appeared to promote polarisation as well as development of morphological features critical for light detection, namely formation of inner and well stacked outer segments oriented towards the retinal pigment epithelium. Putative synapse formation and graft function was evident both at a structural and electrophysiological level. Overall, these results show that human photoreceptors interact readily with a partially degenerated retina. Moreover, incorporation into the host retina appears to be beneficial to graft maturation, polarisation and function.

Details

Original languageEnglish
Article numbere154619
Number of pages19
JournalThe Journal of clinical investigation
Volume132
Issue number12
Early online date28 Apr 2022
Publication statusPublished - 28 Apr 2022
Peer-reviewedYes

External IDs

Mendeley a08e43f6-39f9-3b32-96a2-6c69195ccbb4
Scopus 85130349453
WOS 000814089100002
unpaywall 10.1172/jci154619
ORCID /0000-0001-5624-1717/work/142239046
ORCID /0000-0002-0926-6556/work/142250478
ORCID /0000-0001-9467-7677/work/161888179

Keywords

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Sustainable Development Goals

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Keywords

  • Animals, Ependymoglial Cells, Humans, Induced Pluripotent Stem Cells/transplantation, Mice, Photoreceptor Cells, Vertebrate/metabolism, Retina/metabolism, Retinal Cone Photoreceptor Cells, Retinal Degeneration/metabolism

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