Regenerative capacity of the corneal transition zone for endothelial cell therapy

Abstract

The corneal endothelium located on the posterior corneal surface is responsible for regulating stromal hydration. This is contributed by a monolayer of corneal endothelial cells (CECs), which are metabolically active in a continuous fluid-coupled efflux of ions from the corneal stroma into the aqueous humor, preventing stromal over-hydration and preserving the orderly arrangement of stromal collagen fibrils, which is essential for corneal transparency. Mature CECs do not have regenerative capacity and cell loss due to aging and diseases results in irreversible stromal edema and a loss of corneal clarity. The current gold standard of treatment for this worldwide blindness caused by corneal endothelial failure is the corneal transplantation using cadaveric donor corneas. The top indication is Fuchs corneal endothelial dystrophy/degeneration, which represents 39% of all corneal transplants performed. However, the global shortage of transplantable donor corneas has restricted the treatment outcomes, hence instigating a need to research for alternative therapies. One such avenue is the CEC regeneration from endothelial progenitors, which have been identified in the peripheral endothelium and the adjacent transition zone. This review examines the evidence supporting the existence of endothelial progenitors in the posterior limbus and summarizes the existing knowledge on the microanatomy of the transitional zone. We give an overview of the isolation and ex vivo propagation of human endothelial progenitors in the transition zone, and their growth and differentiation capacity to the corneal endothelium. Transplanting these bioengineered constructs into in vivo models of corneal endothelial degeneration will prove the efficacy and viability, and the long-term maintenance of functional endothelium. This will develop a novel regenerative therapy for the management of corneal endothelial diseases.

Keywords: Cornea endothelium; Corneal endothelial progenitors; Schwalbe’s line, transitional zone, corneal endothelial cell degeneration.

Fig. 1

Human transition zone variation. a Typical TZ morphology with distinguishable smooth TZ (double-head arrows) between PE with cobblestone pattern of endothelial cells and TM with trabeculae inserts and bridges. b Indistinguishable TZ with an unclear border of PE. c Wide TZ with average width > 500 μm. d Absence of TZ, with a deep cleft located between TM and PE. CEC, corneal endothelial cells; PE, peripheral endothelium; TM, trabecular meshwork; TZ, transition zone; M, male; F, female. Scale bars, 300 μm

Fig. 2

Serial block face-scanning electron microscopy of the junction between TZ and PE and 3D reconstruction. a Batch-aligned pack of transmission electron microscopy (TEM) slices showing an overview of PE/TZ junction. b 3D reconstructed image of TZ/PE junction showing DM insertion below the TZ surface. c En face view showing the TZ surface overlaying the DM. d Posterior view showing the insertion of DM beneath TZ. Blue, DM; purple, TZ surface; green, TZ surface cells; brown, endothelial cells; DM, Descemet’s membrane; PE, peripheral endothelium; TM, trabecular meshwork; TZ, transition zone. Scale bars, 30 μm

Fig. 3

TZ in different animal species. a Mouse and b rat with indistinguishable TZ. Insets showing a lack of TZ structure. Insets and magnified images. c Rabbit and d porcine TZ with a clear smooth zone between PE and TM (double-head arrows). PE, peripheral endothelium; TM, trabecular meshwork; TZ, transition zone. Scale bars, 300 μm