Category: Research

Month: 11 Feb 2018

Issue: not yet available

Stem cell researchers characterize RPE maturation processes required in order to maximise potential of transplanted cells.

Collaborative research, led by investigators at the Institute of Molecular Physiology, Johannes-Gutenberg University, Mainz, Germany, and the US National Eye Institute, NIH, Bethesda, Maryland, have shown that the success of transplantation of stem cell derived RPE to the retina is critically dependent on correctly functioning RPE cilia. The study is published in Cell Reports 22, 189–205, Jan 2 2018. The research focused on culturing induced pluripotent stem cell (iPSC) derived RPE from but found that such cells frequently got “developmentally stuck”, failing to mature into normal RPE that were able to faithfully nourish and support the primary photoreceptors. If such stem cell type therapies are to reach the clinic, the fundamental physiology of the RPE would need to be corrected.

 

The researchers worked with iPSC-derived RPE to replace dysfunctional RPE which may be found across several retinal disorders, including geographic atrophy. Models studied included RPE cells derived from ciliopathy patients with Joubert syndrome and specific knock-down and knock-out animal systems, together with experiments designed to gather pharmacological evidence showing that ciliogenesis allowed RPE maturation to progress correctly, resulting in the correct polarization of the cells. In addition, the researchers showed that in cells from ciliopathy patients, defects in the RPE maturation process preceded photoreceptor degeneration. The researchers also demonstrated that the ubiquitous signaling pathway, WNT, mediates the RPE maturation process, whereby WNT suppression is required for maturation but in itself is not sufficient for maturation to occur. The results also indicated that PKCd activation was required to insure actin-cytoskeleton rearrangements that resulted in the correct polarization of the cells. Identifying these processes allows for the pharmacological enhancement of ciliogenesis, which in turn can be applied to culturing of the iPSC derived RPE prior to implantation. Improving the differentiation of such stem cell derived RPE will be a critical step in the development of a potential cell therapy for disorders such a geographic atrophy, and other dysfunctional retinal diseases.

 

The research presents a comprehensive body of cell biology data setting out some key parameters that may be required for the translation of stem cell based strategies to the clinic. Commenting on the work, the authors conclude their paper on a note of caution for future gene therapy trials stating, “this work has helped develop mature and polarized iPSC-RPE for autologous cell therapy of AMD patients and also highlights other considerations when developing treatment strategies for retinal degeneration in ciliopathy patients—that a combined defect in RPE and photoreceptors likely underlies the mechanism for ciliopathy-induced retinal degeneration—and suggests a cautionary note for gene therapy trials that aim to only target photoreceptors because they may only work in select mutations that do not affect the RPE”.

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by Dr. Gearóid Tuohy   Dear EURETINA Members,   A very warm welcome to the June 18th, 2018 edition of EURETINA’s web-based digital magazine, “EURETINA Brief”.  EURETINA are delighted to continue our delivery of up-to-date summary briefs on a range of topics of interest to retinal clinicians, specialists and researchers across Europe. This resource is […]