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Editors Selection IGR 16-4

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Comment by Paul Kaufman 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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Over thirty years ago, several research groups reported that in humans the number of cells in the TM declined with age,¹ and that in POAG either the decline accelerated or the affected individuals started out with fewer cells early in life.²

Subsequently, other groups reported that actomyosin contractility and TM and inner wall SC endothelial cellular and overall TM/SC contraction/relaxation were important regulators of outflow resistance and could be manipulated pharmacologically to therapeutic advantage in glaucoma.³ More recently, still others have elucidated signaling mechanisms emanating from mechanical distention and mechanico-reception in the TM that promote a homeostatic drive toward a set point for outflow resistance and thereby for intraocular pressure (IOP).⁴

The current authors have provided another quantum leap forward in our understanding of the outflow physiology, pathophysiology and perhaps glaucoma therapeutics. They were able to deplete cells from the TM in cultured perfused human anterior segments and show that outflow resistance increased, and then perfuse those depleted anterior segments with cultured HTM cells and show restoration of normal resistance. Most astonishing and important, they showed that iPS cells derived from skin fibroblasts and then perfused into depleted segments assumed the characteristics of TM cells and restored the elevated resistance to normal and also restored the normal homeostatic response to an increased perfusion/elevated IOP.

iPS cells derived from skin fibroblasts and then perfused into depleted segments assumed the characteristics of TM cells and restored the elevated resistance to normal and also restored the normal homeostatic response to an increased perfusion/elevated IOP

The latter raises the exciting possibility of stem-cell therapy for glaucoma by restoring normal function to an aging, diseased trabecular meshwork using the patient's own iPS cells - a truly personalized therapy that bypasses the need for a genetic understanding of the disease, as well as perhaps bypassing the need for topical IOP-lowering medication, laser treatment or surgery, with all their pitfalls. Obviously this will not be all-or-none for many patients, but it would be a huge advance.

I would quibble with a few points in the article: 1) Dismissing gene therapy as a therapeutic strategy because of the complexity of glaucoma genetics is the same mistake that gene hunters for this disease often make, namely that one cannot tweak a compensatory mechanism genetically to therapeutic advantage without ever knowing what has misfired genetically. 2) The authors have historically focused their research on the ECM, and view the ECM as central to understanding TM physiology and glaucoma pathophysiology in that light. It is equally likely that TM cell and organ contractility/relaxation are at least as important, and of course the possibilities for interactions between these 'players' are infinite. And this does not even get into the realm of the 'poor people' and those who believe that resistance lies primarily in the inner canal wall endothelium rather than the outer JCT. Perhaps we should be (re)generating SC inner wall cells rather than or in addition to TM cells in our poor, aging, sick conventional outflow pathway! However, these are side issues in the present context of a seminal piece of work.

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