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Transplanted human cones incorporate into the retina and function in a murine cone degeneration model
Sylvia J. Gasparini, … , Mike O. Karl, Marius Ader
Sylvia J. Gasparini, … , Mike O. Karl, Marius Ader
Published April 28, 2022
Citation Information: J Clin Invest. 2022;132(12):e154619. https://doi.org/10.1172/JCI154619.
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Research Article

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

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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 for use in clinical practice. Unlike the unstructured grafts of prior cell-suspension transplantations into end-stage degeneration models, we describe the extensive incorporation of induced pluripotent stem cell (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 polarization as well as the development of morphological features critical for light detection, namely the formation of inner and well-stacked outer segments oriented toward the retinal pigment epithelium. Putative synapse formation and graft function were evident at both structural and electrophysiological levels. Overall, these results show that human photoreceptors interacted readily with a partially degenerated retina. Moreover, incorporation into the host retina appeared to be beneficial to graft maturation, polarization, and function.

Authors

Sylvia J. Gasparini, Karen Tessmer, Miriam Reh, Stephanie Wieneke, Madalena Carido, Manuela Völkner, Oliver Borsch, Anka Swiersy, Marta Zuzic, Olivier Goureau, Thomas Kurth, Volker Busskamp, Günther Zeck, Mike O. Karl, Marius Ader

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Figure 4

Minimal donor-host interaction, polarization, or maturation in D250 grafts.

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Minimal donor-host interaction, polarization, or maturation in D250 graf...
Cryosections of retina transplanted with mCar-GFP+ cells on D250 after differentiation showed (A) minimal donor-host interaction and few mitochondria-rich outgrowths, (B) little PRPH2 staining, (C) dispersed PNA binding, and (D) mislocalized L/M-opsin staining. TEM of the D250 transplanted cones showed (E) few inner segments (IS) and (F) occasional disorganized outer segments (OS). (G) A similar number of cells (~20,000 cells) survived in D200 plus 10-week and D250 plus 10-week samples. Scale bars: 50 μm (IHC images) and 2 μm (TEM images).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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