Mimicking Retinal Development and Disease With Human Pluripotent Stem Cells

Abstract

As applications of human pluripotent stem cells (hPSCs) continue to be refined and pursued, it is important to keep in mind that the strengths and weaknesses of this technology lie with its developmental origins. The remarkable capacity of differentiating hPSCs to recapitulate cell and tissue genesis has provided a model system to study stages of human development that were not previously amenable to investigation and experimentation. Furthermore, demonstration of developmentally appropriate, stepwise differentiation of hPSCs to specific cell types offers support for their authenticity and their suitability for use in disease modeling and cell replacement therapies. However, limitations to farming cells and tissues in an artificial culture environment, as well as the length of time required for most cells to mature, are some of the many issues to consider before using hPSCs to study or treat a particular disease. Given the overarching need to understand and modulate the dynamics of lineage-specific differentiation in stem cell cultures, this review will first examine the capacity of hPSCs to serve as models of retinal development. Thereafter, we will discuss efforts to model retinal disorders with hPSCs and present challenges that face investigators who aspire to use such systems to study disease pathophysiology and/or screen for therapeutics. We also refer readers to recent publications that provide additional insight and details on these rapidly evolving topics.

Bestrophinopathy: An RPE-photoreceptor interface disease

“…Considering the rapid progress in hiPSC research, the key insights from a reliable animal model and its immediate verification in patient-specific hiPSC-RPE generate an exceptional momentum that will accelerate progress to the clinical applications (Guziewicz et al, 2013; Sinha et al, 2016). As a complementary system, hiPSC-RPE-based in vitro modeling of BVMD provides a platform for assessing pharmacological and gene therapy based interventions (e.g., lengthening of apical microvilli as a therapeutic outcome measure).…”

Two-photon polymerization for production of human iPSC-derived retinal cell grafts

“…Assuming that the relationship between scaffold volume and printing time is linear, we can use the time-optimized printing parameters to create a full-size scaffold (roughly 5 mm in diameter) in less than 2 days. This period is reasonable given that it takes much longer than this to differentiate the cells needed to seed such a graft [25–27]. Furthermore, our results indicate that at these conditions, large scaffolds will have intact horizontal pores and that tuning the size of vertical pores will not significantly affect the margin of error for pore size.…”

Regenerative medicine in the retina: from stem cells to cell replacement therapy

“…With the dawn of stem cell research, the constraints posed by the reliance on primary tissue were lifted by the possibility for maintenance of retinal neurons in vitro , 35 closely followed by the de novo differentiation of retinal neurons from either ES or iPS cell lines, the strategy for which turned out to be functionally conserved across species, including humans. 36 , 37 Initially relying on two-dimensional adherent neural rosette structures or simple monolayers [ Figure 2(c) and Table 2 ], 38 – 42 retinal differentiation protocols quickly diversified to suspension cultures, utilizing the formation of simple embryoid bodies (spheroids) or complex three-dimensional retinal organoids [ Figure 2(a) and (b) and Table 2 ]. 37 , 43 – 47 Aside from those physical aspects, critical for scale-up and manufacture of clinical grade products, culture strategies vary with respect to their underlying molecular approach to differentiation.…”