Concise Review: Human Induced Pluripotent Stem Cell Models of Retinitis Pigmentosa

Abstract

Hereditary retinal dystrophies, specifically retinitis pigmentosa (RP) are clinically and genetically heterogeneous diseases affecting primarily retinal cells and retinal pigment epithelial cells with blindness as a final outcome. Understanding the pathogenicity behind these diseases has been largely precluded by the unavailability of affected tissue from patients, large genetic heterogeneity and animal models that do not faithfully represent some human diseases. A landmark discovery of human induced pluripotent stem cells (hiPSCs) permitted the derivation of patientspecific cells. These cells have unlimited self-renewing capacity and the ability to differentiate into RP-affected cell types, allowing the studies of disease mechanism, drug discovery, and cell replacement therapies, both as individual cell types and organoid cultures. Together with precise genome editing, the patient specific hiPSC technology offers novel strategies for targeting the pathogenic mutations and design therapies toward retinal dystrophies. This study summarizes current hiPSC-based RP models and highlights key achievements and challenges of these cellular models, as well as questions that still remain unanswered. STEM CELLS 2018;36:474-481 SIGNIFICANCE STATEMENTHereditary retinal dystrophies including retinitis pigmentosa (RP) are clinically and genetically heterogeneous disease affecting primarily retinal cells and retinal pigment epithelial cells, with blindness as a final outcome. Discovery of human induced pluripotent stem cells (hiPSCs) permitted the derivation of patient-specific stem cells with unlimited self-renewing capacity and ability to differentiate into RP-affected cell types allowing studies of disease mechanism, drug discovery, and cell replacement therapies both as individual cell types and organoid cultures. Together with precise genome editing in these cells, this study can correct the pathogenic mutations and design therapies to cure these diseases. This study summarizes current hiPSCbased RP models discussing the major achievements as well as challenges about these cellular models.

Thyroid hormone signaling specifies cone subtypes in human retinal organoids

“…Expression of thyroid hormone-regulating genes suggests that retina-intrinsic temporal control of thyroid hormone levels and activity governs cone subtype specification. Whereas retinal organoids have largely been studied for their promise of therapeutic applications (15), our work demonstrates that human organoids can also be used to reveal fundamental mechanisms of human development.…”

Pre-mRNA Processing Factors and Retinitis Pigmentosa: RNA Splicing and Beyond

“…By transduction of Yamanaka factors Oct3/4, Sox2, Klf4, c-Myc, patient-derived somatic cells are converted into pluripotent, embryonic-like state with the capacity of unlimited self-renewal and multilineage differentiation, enabling the rapid establishment of disease-specific cell models. These models are widely used for the studies of disease mechanisms, toxicological assay, drug screening, and cell replacement therapies ( Artero Castro et al, 2018 ).…”

Inducible Pluripotent Stem Cells to Model and Treat Inherited Degenerative Diseases of the Outer Retina: 3D-Organoids Limitations and Bioengineering Solutions

“…In the first one, we will recapitulate the main issues in drug development and cell replacement strategies to treat or cure IRD in order to restore vision (reviewed in [ 8 ]). In the same section, we will focus on the potential of inducible pluripotent stem cells (iPS) and iPS-derived three-dimensional (3D) retinal organoids (ROs) to promote drug development [ 9 , 10 , 11 , 12 , 13 ] and substitutive approaches to IRD by improving disease modeling [ 9 , 10 , 11 , 12 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ] and cell replacement therapies [ 12 , 25 , 26 , 27 ].…”