Drusen on Demand? Authors Describe a Novel Culture System for Generating subRPE Deposits

In age-related macular degeneration (AMD), extracellular complexes including drusen and diffuse (basal laminar and basal linear) deposits accumulate beneath the retinal pigment epithelium (RPE). Due to their compelling association with AMD, a better understanding of the molecular and cellular basis of drusen formation is needed. Pilgrim and colleagues evaluated a novel culture system, using polarized porcine RPE cells on 10-lm polyester filters, for modeling subRPE AMD-associated deposits. How comprehensively these deposits biochemically recapitulate drusen remains to be fully determined, but in addition to ApoE and drusen-associated lipids, these subRPE accumulations contain insoluble hydroxyapatite, recently suggested to nucleate drusen accretion. Some of the deposits are elevated, with remarkable resemblance to human drusen (e.g., Figure 8A in Ref. 1). The authors also compared human fetal RPE and porcine primary cultures and found similar ApoE deposition between these cell types on the 10-lm platform; in light of the ethical reservations that many policymakers and other stakeholders have in employing human fetal tissue for research, the ability to adapt other cell sources is an advance. Another of the many positive features of this technique is that it allows for the distillation of a very complex system into relatively few components—still extremely complex but more manageable—that can be studied independently. It also raises several questions: If the RPE normally secretes drusenoid material, why is this accumulation so rapid in culture, with visible deposits in weeks rather than the decades required in vivo? Is subRPE debris normally produced in young eyes, but with efficient removal at an equal rate? Does this suggest a role for the healthy choriocapillaris and/or macrophages to clear debris that is generated by normally functioning RPE? A robust, in vitro system will allow for further exploration of drusen biogenesis and enable these and other interesting and translationally meaningful questions to be tackled.