Cellular processes underlying glaucoma identified using stem cells

Stepwise differentiation of retinal ganglion cells from human pluripotent stem cells enables analysis of disease processes and raises potential for treatment strategies.

Mar 24, 2016

Glaucoma, a relatively common condition which affects retinal ganglion cells (RGCs), can lead to optic nerve damage and vision loss if left untreated. Optic nerve injuries can also be caused by collisions in contact sports or combat injuries in soldiers. A new study conducted by researchers from Indiana University–Purdue University Indianapolis (IN, USA) has given hope for a potential treatment for these conditions through the use of stem cells.

In the study, researchers led by Jason Meyer (Indiana University–Purdue University Indianapolis) took skin cells biopsied from volunteers with an inherited form of glaucoma as well as from control volunteers without the disease. These cells were genetically reprogrammed to become pluripotent stem cells, which subsequently underwent directed stepwise differentiation to become RGCs, causing the cells to develop RGC-specific features that were observed to be different between glaucoma and control volunteers.

"Skin cells from individuals with glaucoma are no different from skin cells of those without glaucoma," explained Meyer. "However, when we turned glaucoma patients' skin cells into stem cells and then into RGCs, the cells became unhealthy and started dying off at a much faster rate than those of healthy individuals. Now that we have produced cells that develop features of glaucoma in culture dishes, we want to see if compounds we add to these RGCs can slow down the degeneration process or prevent these cells from dying off. We already have found candidates that look promising and are studying them.

Highlighting the groups’ vision for the future of their work, Meyer stated: “In the more distant future, we may be able to use healthy patient cells as substitute cells as we learn how to replace cells lost to the disease. It's a significant challenge, but it's the ultimate – and, we think, not unrealistic – long-range goal”.

– Written by Hannah Wilson

Source: Indiana University–Purdue University Indianapolis news release: http://news.iupui.edu/releases/2016/03/stem-cells-cellular-processes-glaucoma.shtml


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The importance of logic in experimental science can sometimes be overlooked when it might be very important for making the right conclusion. This report seems a case in point.

A group A versus group B study, like this one, is highly biased when not blinded. The study begins with the investigators knowing that the A and B groups differ for glaucoma status. So, when a difference is noted between the A and B groups, bias attributes it to the known disease difference, when in fact it could be due to any number of other unknown differences between groups A and B. Case in point, since as reported here, the differences in cell death appear to be spontaneous, why didn't the authors conclude that cells from glaucoma-free individuals survive better, instead of concluding the cells from glaucoma patients die at a faster rate? What is the baseline? It is actually arbitrary, but certainly influenced by the investigators' glaucoma disease perspective (i.e., their bias).

Beyond the bias, where is the logic concern? Well, the authors begin their study with the concept that glaucoma (with its high ocular pressure) leads to the injury of RGCs with ensuing blindness. But now that RGCs developed from skin cell-derived iPSCs die faster spontaneously, shouldn't the authors, logically, consider that an intrinsic defect in RGCs may be causing the high ocular pressure that is pathognomonic of glaucoma?

Of course, this seeming chicken-egg logic problem may itself derive from the bias of the starting conclusion that the difference in the in vitro viability of iPSC-derived RGCs from glaucoma versus glaucoma-free subjects is cause-effect related to difference in disease status.

So, the solution here is to treat the new association as the basis for not a conclusion, but instead for a new hypothesis that a cause-effect relationship operates. For this, the authors should first reduce their investigator bias with a better experimental design and then conduct experiments that go beyond associations to test for cause-effect relationships.

James L. Sherley, M.D., Ph.D.
Asymmetrex, LLC

One follow-up point: If the study were blinded, some investigator bias would be reduced; but the more fundamental problem of binomial disease association bias would remain.

James L. Sherley, M.D., Ph.D.
Asymmetrex, LLC