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Using Patient iPSC-derived Retinal Pigment Epithelial Cells to Evaluate Differential Susceptibility to MEK
Purpose:
Compare the effect of MEK inhibition on iPSC-derived retinal pigmental epithelial (RPE) cells generated from a patient who developed MEK inhibitor-Associated Retinopathy (MEKAR) versus a patient who did not develop retinopathy.
Design:
Case-control.
Subjects:
Two female patients with Neurofibromatosis Type 1 who were treated with MEK inhibitors. One patient developed MEKAR, the other did not.
Methods:
RPE were generated from human induced pluripotent stem cells (hiPSCs) from these two patients. These hiPSC-derived RPE were treated with selumetinib for 10 days.
Main Outcome Measures:
Phagocytic activity and changes in gene expression.
Results:
As previously reported, there was a significant increase in internalized rhodopsin in phagocytosis assays, yet this was only found in hiPSC-derived RPE from the patient who developed MEKAR. Selumetinib decreased expression of genes related to fluid transport and cell volume, including aquaporins and solute transporters. At baseline, cells from the patients without MEKAR had higher expression of these genes. Interestingly, selumetinib-induced changes in gene expression only reached statistical significance in cells from the patient who did not develop MEKAR, suggesting these changes may be a compensatory protective mechanism. Patients susceptible to forming MEKAR may have increased phagocytosis without a compensatory change in expression of genes related to fluid flux, thereby inhibiting their ability to transport fluid out of the subretinal space.
Conclusions:
MEK inhibitor-Associated Retinopathy may only affect susceptible patients whose retinal pigment epithelium cannot sufficiently regulate expression of genes related to fluid transport and cell volume, altering the ability of these cells to properly function.
Insights
MEK inhibitor-associated retinopathy (MEKAR) may stem from a patient's inability to regulate fluid transport genes in retinal pigment epithelium. This dysfunction, observed in iPSC-derived RPE cells, highlights a potential mechanism for MEKAR development in susceptible individuals.
Area of Science:
- Ophthalmology
- Cell Biology
- Pharmacology
Background:
- MEK inhibitors are used to treat conditions like Neurofibromatosis Type 1.
- MEK inhibitor-Associated Retinopathy (MEKAR) is a potential side effect of these treatments.
- The underlying cellular mechanisms of MEKAR are not fully understood.
Purpose of the Study:
- To compare the effects of MEK inhibition on induced pluripotent stem cell (iPSC)-derived retinal pigmental epithelial (RPE) cells.
- To investigate differences between RPE cells from a patient who developed MEKAR and one who did not.
- To elucidate the cellular basis of MEK inhibitor-associated retinopathy.
Main Methods:
- Generated iPSC-derived RPE cells from two female patients with Neurofibromatosis Type 1, one with MEKAR and one without.
- Treated these hiPSC-derived RPE cells with selumetinib (a MEK inhibitor) for 10 days.
- Assessed phagocytic activity and gene expression changes.
Main Results:
- hiPSC-derived RPE from the patient who developed MEKAR showed increased internalized rhodopsin, indicating impaired phagocytosis.
- Selumetinib treatment decreased expression of fluid transport and cell volume genes (e.g., aquaporins) in RPE cells.
- Gene expression changes were statistically significant only in cells from the patient who did not develop MEKAR, suggesting a compensatory protective mechanism.
Conclusions:
- MEK inhibitor-Associated Retinopathy may affect susceptible patients whose RPE cells cannot adequately regulate fluid transport and cell volume genes.
- This dysregulation in gene expression can impair RPE cell function and contribute to retinopathy development.
- Understanding these cellular mechanisms could inform strategies to prevent or manage MEKAR.
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