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Editors Selection IGR 9-2

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Comment by Terete Borras on:

59479 Induced pluripotent stem cells restore function in a human cell loss model of open-angle glaucoma, Abu-Hassan DW; Li X; Ryan EI et al., Stem Cells, 2015; 33: 751-761

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The authors of this manuscript report a breakthrough finding that could open the door to the use of stem cells for the treatment of glaucoma. They have put together a well thought out procedure to differentiate induced pluripotent human stem cells (iPSC) to trabecular meshwork cells in culture, graft them into the trabecular meshwork tissue in perfused post-mortem human eyes and obtain restoration of their homeostatic response to pressure. The study is important for several different reasons. The continuously referred to as well-established phenomenon of loss of TM cellularity with age and in glaucoma is still based on two to three studies that are now about thirty years old. Although not their primary goal, their technology could provide a handle to revisit and confirm or not an important old finding, which has not been done. But the true importance is the feasibility of a potential new treatment.

The study comprises two arms. In one, the authors use commercially available human iPSC to show that they can be differentiated into cells which exhibit all morphological and molecular characteristics of trabecular meshwork cells. The cultured cells express the correct stem and trabecular cell markers before and after differentiation, and are able to regain their phagocytic property. In the second part of the study, they show that their new cells can be transplanted to ex vivo living human tissue and acquire one of the key functional properties of the tissue, that of regulating pressure. All these results could only be achieved due to the vast knowledge and experience of the group in trabecular meshwork biology and physiology. They were able to pay attention to every relevant detail. Cell differentiation occurred when using not only conditioned cell media but also conditioned extracellular matrix (ECM). A system to deplete a controlled number cells in situ was carefully developed by the use of saponin, which eliminates the cells but leaves behind their ECM. All controls, including using Q-dots to trace transplanted cells, perfusing undifferentiated dermal fibroblasts and showing size of the frontal sections are in place. One wished though, that details about their tissue processing (frozen sections?) and beams blue autofluorescence had been added. At times, the quantification and localization of the green live cells is not so clear (Fig. 1 B & C). One also wishes that in addition to the normalization of flow to baseline levels, the difference in outflow resistance between the saponin-treated and normal tissues could be seen. Would just the ECM presence matter?

Without resting importance to the relevance of proving and grafting truly differentiated HTM cells in the whole intact tissue, I would see the result as pretty obvious. The cells determine the function of the whole tissue. Less cells, less function. Add more cells and now you see the function. It might not be that the remaining cells have lost their homeostatic ability, but just that it is a matter of detection, or that a reduced number of cells are not able to amount the response levels that the entire tissue requires.

A new beginning that would allow addressing many questions regarding the involvement of cells and ECM in outflow facility regulation, as well and more important, allow thinking on a potential autologous cell treatment for glaucoma. A well-deserved congratulations to the group.

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