Potential role of stromal collagen in cystine crystallization in cystinosis patients

Abstract

Cystinosis is a genetic disease that leads to the accumulation of intracellular cystine crystals in all organs including cornea due to the loss of cystine efflux transporters in the lysosome of the cells. While the mechanism for formation of intracellular cystine is well understood for most organs, it does not explain many observations for crystal accumulation in the cornea of cystinosis patients. First, the crystals in cornea are extracellular and needle-like with several hundred microns length which is in sharp contrast with the rectangular or hexagonal crystals found throughout other organs. Second, these crystals are arranged parallel to the stromal collagen, which is a unique to the cornea. Third, crystal growth in the cornea reaches a saturation point after where no further crystallization occurs. We propose a hypothesis supported by in vitro and ex vivo data to explain these observations. We hypothesize that the stroma crystals form extracellularly due to the ionic interactions between the cystine diffusing into the eye and collagen fibrils present in the stroma. We examine cystine crystal growth both with in vitro polymer solutions and ex vivo in rabbit cadaver eyes to show that negatively charged polymers lead to the formation of more cystine precipitation in aqueous solution and that needle-like cystine crystal formation can be observed only in presence of certain polyelectrolytes including collagen. This proposed mechanism explains many of the yet unanswered questions but it needs further support from in vivo studies. The improved understanding could lead to improved treatment of corneal cystinosis.