Personalisierte Ophthalmologie – induzierte pluripotente Stammzellen als In-vitro-Modellsysteme für degenerative Netzhauterkrankungen

Zusammenfassung

Die Suche nach kausalen Therapieoptionen für degenerative Netzhauterkrankungen kann mit einem detaillierten Verständnis pathologischer Vorgänge gezielt vorangetrieben werden. Alternativ kann sie sich auch auf einen eher ungerichteten Suchansatz für therapeutische Wirkstoffe verlassen. Für beide Forschungsansätze werden In-vitro- und, falls möglich, auch In-vivo-Krankheitsmodelle benötigt, die eine möglichst genaue Abbildung des primären Ortes der Schädigung reflektieren. Tiermodelle unterliegen Einschränkungen und können oft nur dezidierte Aspekte eines komplexen Krankheitsprozesses abbilden. Primärkulturen von Zelltypen des hinteren Augenpols sind lediglich invasiv bzw. post mortem zugänglich und aufgrund ihrer raschen Seneszenz nur ungenügend geeignet für zeitlich anspruchsvolle Analysen oder pharmakologische Suchansätze. Immortalisierte retinale Zelllinien wiederum unterscheiden sich in einigen Aspekten zu sehr von den nativen Zelltypen. Eine vielversprechende Alternative bieten induzierte pluripotente Stammzellen (iPSCs). Sie sind wenig invasiv zugänglich, patientenspezifisch generierbar, uneingeschränkt vermehrbar und können aufgrund ihrer Pluripotenz bereits jetzt in einige retinale Zelltypen gezielt ausdifferenziert werden. Diese iPSC-abgeleiteten retinalen Zellen gleichen nativen Zellen in vielen charakteristischen Schlüsseleigenschaften. In diesem Übersichtsartikel werden bereits etablierte In-vivo-und In-vitro-Krankheitsmodelle degenerativer Netzhauterkrankungen vorgestellt und das Potenzial von iPSCs für eine personalisierte In-vitro-Modellierung ausgeleuchtet. Darüber hinaus werden bisher etablierte iPSC-abgeleitete Zelltypen des hinteren Augenpols – insbesondere Zellen des retinalen Pigmentepithels – detaillierter betrachtet und ein Ausblick für das Potenzial dieser Zellen in der allgemeinen ophthalmologischen Forschung gegeben.

Abstract

Today, the search for therapeutic options to treat retinal degeneration often relies on an in-depth understanding of the underlying pathological events. Alternatively, it is conceivable to search, in an undirected screening approach, for chemical compounds affecting disease outcome. For both approaches, there is an urgent need for in vitro and, ideally, in vivo disease models that adequately reflect the site of pathology. Currently available animal models possess limitations as they often develop only defined aspects of disease. Primary cell cultures, derived from the posterior pole of the eye, can only be obtained after invasive surgery or are available post mortem, but due to rapid cell senescence are not suited for long-term analysis. Immortalized retinal cell lines, on the other hand, differ in many aspects from native cells. In this situation, a promising alternative could arise from induced pluripotent stem cells (iPSCs). This cell species can be generated via non-invasive techniques, they are patient-specific, can be propagated indefinitely, and theoretically can be differentiated in all types of retinal cells due to their pluripotent capacities. Importantly, the iPSC-derived retinal cells greatly resemble native cells in many characteristic traits. In this review we present a selection of established in vivo und in vitro models for retinal degenerative disease. We also discuss the potential of iPSCs for personalized in vitro modelling and provide an overview of existent iPSC-derived cell types of the posterior pole, particularly for cells of the retinal pigment epithelium. We finally give an outlook for the potential of such cells for basic research in ophthalmology.

Schlüsselwörter

Netzhautdegeneration - induzierte pluripotente Stammzellen (iPSC) - Photorezeptor - retinales Pigmentepithel (RPE) - Tiermodell - Krankheitsmodell

Key words

retinal degeneration - induced pluripotent stem cells (iPSC) - photoreceptor - retinal pigment epithelium (RPE) - animal model - disease modelling

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