Induced pluripotent stem cells: An emerging tool for the study of human inherited retinal disease

Abstract

Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) are both valuable sources of retinal cell types for in vitro and in vivo studies. However, unlike hESCs, hiPSCs can be derived from individual patients and therefore offer a unique opportunity to model human retinal disease. Using protocols developed in our laboratory, hiPSCs derived from patients with selected inherited retinal disorders (eg, gyrate atrophy (GA) and Best vitelliform macular dystrophy (BVMD)) and normal controls underwent targeted differentiation to obtain enriched cultures of affected retinal cell types. Thereafter, the retinal cell cultures were examined to determine whether disease-specific phenotypes could be recapitulated in vitro. Molecular, biochemical, and physiological analyses revealed phenotypes in hiPSC-derived cell populations that could be used to test drug efficacy and/or study the underlying disease mechanism(s). For the GA culture model, a deficit in ornithine aminotransferase activity was present in differentiated hiPSC-RPE cells that could be improved with high dose vitamin B6. In the BVMD culture model, hiPSC-RPE cells from affected patients showed greater accumulation of ingested photoreceptor outer segment material and reduced transcellular fluid flux compared to sibling control hiPSC-RPE. Subsequent investigation suggested a role for BESTROPHIN-1, the protein mutated in BVMD, in the regulation of key RPE functions. In designing a hiPSC modeling study, care should be taken to select retinal disorders that have a reasonable expectation of recapitulating key pathophysiological processes in culture. In addition, a means to enrich for cell type(s) targeted by the disease is necessary; otherwise, the task of assuring a reproducible culture environment becomes daunting. Taking these and other limitations of hiPSC modeling into consideration, inherited diseases of the retina remain appealing, particularly monogenetic, early-onset diseases that affect the RPE. As we improve our understanding of complex disorders and our ability to build more intricate culture environments, the number and types of retinal diseases amenable to hiPSC modeling will broaden. hiPSCs represent a new and potentially powerful tool that can help close the gap between our knowledge of the genetics and the biology of inherited retinal diseases. In addition, custom hiPSC retinal model systems could be used to test known therapeutics and develop drug and gene therapy screening platforms. However, limitations exist in any culture system; thus, hiPSC technology is envisioned to complement, not supplant, existing laboratory models of disease.