Wiederherstellung von photopischem Sehen durch Zelltransplantation
Augenheilkunde
Zusammenfassung der Projektergebnisse
Cell-based strategies for the replacement of photoreceptors in retinal degeneration represent promising treatment options for currently incurable blinding diseases. Photoreceptor transplantation has been shown to repair retinal function to some extent in mouse models of retinal degeneration. Therefore, it is considered as a potential cell replacement treatment option for retinopathies characterized by photoreceptor loss such as retinitis pigmentosa or age-related macular degeneration. However, in contrast to the nocturnal mouse retina, that is dominated by rod photoreceptors, human daylight vision depends mainly on cones. Therefore, the number of transplantable cones that can be isolated from the mouse retina is severely limited circumventing to evaluate the potential of cell-based therapies to treat daylight vision loss. In this project, we established a comprehensive source of cone-like photoreceptors from transgenic mice deficient in the transcription factor neural retinal leucine zipper (Nrl-/- mouse), a rod-determining factor. The retinas of Nrl-/- mice consist solely of cone and cone-like photoreceptors and these were used for transplantation into a mouse model of cone degeneration. Our results show robust survival and maturation of donor cone-like cells in the host retina for up to six months. Importantly, individual retinal ganglion cell recordings demonstrated the restoration of photopic responses in cone degeneration mice following transplantation suggesting, for the first time, the feasibility of daylight vision repair by cell transplantation in the adult mammalian retina. Unexpectedly, we additionally identified a novel form of cell-cell communication between transplanted donor and host photoreceptors. By using (i) single cell analysis using imaging flow cytometry, (ii) a Cre/LoxP fusion assay, and (iii) separating cytoplasmic from nuclear labelling we demonstrated that after retinal transplantation the majority of grafted photoreceptors do not structurally integrate into the recipient tissue but instead exchange cellular material with host photoreceptors. Functional repair via photoreceptor transplantation might therefore be achieved by two ways: (1) replacement of lost photoreceptors in severely degenerated retinas where the majority of photoreceptors have been lost (cell replacement therapy) or (2) transfer of cytoplasmic material from donor to host photoreceptors in conditions, where endogenous photoreceptors are dysfunctional but still existing (cell support therapy). Beside publication in peer-reviewed scientific journals, our work was recognised in consumer press including Sächsische Zeitung (SZ, 17.02.2014), Dresdner Neueste Nachrichten (DNN, 21.10.2014), Wirtschaftswoche (9.4.2016), and Mitteldeutscher Rundfunk (MDR, Aktuelle Kamera; 27.06.2017).
Projektbezogene Publikationen (Auswahl)
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(2015) Daylight vision repair by cell transplantation. Stem Cells. 33(1):79-90
Santos-Ferreira T, Postel K, Stutzki H, Kurth T, Zeck G, Ader M
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(2016) Retinal transplantation of photoreceptors results in donor-host cytoplasmic exchange. Nat Commun, 7:13028
Santos-Ferreira T, Llonch S, Borsch O, Postel K, Haas J, Ader M
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(2016) Stem cell-derived photoreceptor transplants differentially integrate into mouse models of cone-rod dystrophy. IOVS. 57(7):3509-20
Santos-Ferreira T, Völkner M, Borsch O, Haas J, Cimalla P, Vasudevan P, Carmeliet P, Corbeil D, Michalakis S, Koch E, Karl MO, Ader M
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(2017) [Photoreceptor Transplantation into the Degenerative Retina]. Klin Monbl Augenheilkd, 234(3):343-353
Borsch O, Santos-Ferreira T, Ader M
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(2017) Rebuilding the Missing Part - A Review on Photoreceptor Transplantation. Front Syst Neurosci, 10:105
Santos-Ferreira TF, Borsch O, Ader M
