Autologous Cell Replacement
Unlike the neural retina of amphibians and other lower vertebrates, when injured the human retina is incapable of regenerating. For this reason, death of the light-sensing rod and cone photoreceptor cells, which is a hallmark of retinal degenerative diseases such as Stargardt disease, retinitis pigmentosa and age-related macular degeneration (below), results in irreversible vision loss. One of the most promising approaches currently under development for the treatment of retinal degenerative blindness is stem cell–based photoreceptor cell replacement.
A variety of different donor cell types ranging from embryonic and induced pluripotent stem cells, which require differentiation prior to transplantation, to fetal-derived retinal progenitors and postmitotic photoreceptor precursor cells have been used with varying degrees of success. Although retinal progenitor and postmitotic photoreceptor precursor cells are at the ideal point in retinal development for optimal cellular integration and post-transplant maturation into new functional photoreceptor cells, for a variety of ethical, immunologic, and logistical reasons it is difficult to envision a strategy in which these cells could be directly isolated from postmortem donors and transplanted into patients.
Induced pluripotent stem cells (iPSC), which can be generated from a patients own somatic cells (eg., skin derived fibroblasts, see below), are the ideal stem cell type for this application.
Using either 2D (below A-E) or 3D (below F-J) differentiation protocols we can readily generate retinal tissue that contains transplantable rod and cone photoreceptor cells.
In 2011 we demonstrated that iPSC derived photoreceptor cells generated from mice have the ability to integrate with the dystrophic retina of a rhodopsin deficient host, resulting in partial restoration of electro retinal function.
with inner and outer segments (left, red). For patients with advanced disease, who suffer from extensive photoreceptor cell loss, death of the underlying RPE and choroidal vasculature can occur. Similarly, for patients with diseases such as AMD and choroidaremia, death of choroidal endothelial and RPE cells precedes photoreceptor cell loss. In both cases engineered multilayered grafts containing photoreceptor (above), RPE (below A-C) and choroidal vasculature (below D-G) will likely be the required for sustained restoration of vision.
In 2013 we demonstrated that we could generate human retinal cups that contained RPE and photoreceptor cells. Following isolation and transplantation into the subretinal space of a mouse model of retinitis pigmentosa we further demonstrated that these newly generated cells couldintegrate within the host outer nuclear layer giving rise to new mature photoreceptor cells