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Glaucoma Dialogue IGR 16-3

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Comment by Yiqin Du 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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Abu-Hassan and colleagues reported a research study about cell treatment to repopulate the cellularity of the trabecular meshwork (TM) and restore the intraocular pressure (IOP) homeostatic response to high pressure in an anterior segment organ culture system.

Under normal conditions, the outflow pathway responds to high pressure and increases flow rate to maintain IOP at normal range, maintaining a certain flow of uL/min/mmHg (outflow facility). When the response is compromised, IOP may increase.

The authors conducted an acute TM cell depletion model by perfusing saponin to destroy a portion of the TM cells. Using an optimized concentration of saponin to perfuse for seven minutes, the percentage of TM cells remaining was comparable to that present in glaucomatous TM. Repopulation of the damaged TM cells in the organ culture model by applying primary TM cells or TM-like cells induced from iPSCs could restore the IOP homeostatic function. In contrast, other cell types, such as dermal fibroblasts, not-differentiated iPSC embryoid bodies and human umbilical vein endothelial cells, did not restore the homeostasis. iPSCs were induced into TM-like cells by culture on extracellular matrix (ECM) produced by TM cells and in a medium conditioned by TM cells for 30 days.

Although still in a preliminary phase, this is a remarkable study which opens a door for cell-based therapy to replenish the TM and regulate IOP using autologous cells. It has been previously shown that TM cellularity reduction is associated with open-angle glaucoma. There was previously no direct evidence to show that cellular replacement to the TM could restore normal outflow facility and regulate IOP. Abu-Hassan and colleagues conducted the experiment to show that exogenous TM cells or TM-like cells derived from iPSCs could integrate to all layers of the TM tissue and restore the IOP homeostatic function.

But there is still a long way to go in order to translate TM cell transplantation for clinical treatment of glaucoma. The TM cell death induced by saponin treatment is an acute response whereas the cellularity reduction in glaucoma is a chronic process with ECM changes in the outflow pathway. The authors detected cell death in glaucomatous TM tissue. It is unclear if the TM cells continuously undergo apoptosis and necrosis while self-regeneration is ongoing or altogether absent in glaucoma patients. On the other hand, is there TM cell apoptosis and necrosis and what is the self-regeneration condition and potential in normal population?

In this study, perfused exogenous cells were able to restore TM function in such a short period. The cell replacement is an acute cellular attachment rather than chronic remodeling. What are the mechanisms for the restoration? Did the cells deposit any specific ECM, which is essential to regulate IOP, in such a short period? To have an ex vivo or in vivo model mimicking the chronic glaucoma pathology is still challenging and function of repopulated cells on the ECM remodeling and outflow regulation needs to be explored.

Again, this study is a short-term observation. For long-term effects and considering the lifespan of transplanted cells, what cell types are the best: primary TM cells, stem cells from TM, progenitors of TM cells derived from iPSCs, or fully differentiated TM-like cells from iPSCs?

There is a concern about the differentiation efficiency from iPSCs to TM-like cells. iPSCS, similar to embryonic stem cells, are in the very early immature stage. On the other hand, TM cells are functionally fully differentiated cells. There are many cell developmental stages between them. Simply induction in one step would be ideal, but the efficiency is also a big concern.

Along the cell-based therapy, there is still huge work to do. But this study is exciting in validating the concept that cellular repopulation of the diseased TM could restore outflow homeostasis and control IOP.

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