# Tissue Engineering Strategies for Retina Regeneration
## 2 Cell Types Used for Therapies in the Eye  
Initial transplantation studies using autologous RPE sheets and RPE isolated from fetal or adult donor eye tissue showed \"proof of concept\" for photoreceptor preservation and visual functional improvement in human patients [14; 15; 16; 17; 18; 19; 20; 21]. Later, transplantation of different stem cell suspensions of the neuronal and non-neuronal lineage including mesenchymal stem cells from umbilical cord [22; 23], bone marrow [24; 25; 26], adipose tissue [27], human neural progenitor cells [28], embryonic stem cell (ESC)-derived neural progenitors [29], iris pigment epithelium (IPE) derived cells [30; 31], and RPE [32; 33] were shown to provide trophic support and visual functional improvement in preclinical models of RD diseases. Protocols to differentiate human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) to RPE, retinal progenitor cells (RPC), photoreceptor precursor cells, and retinal organoids (RO) have been successfully established by various investigators [34; 35; 36; 37; 38; 39; 40; 41].  
The RPE cells derived from pluripotent stem cells (PSC) form a monolayer of pigmented cells and show typical features of RPE such as polarity, tight junction formation, and phagocytosis of photoreceptor outer segments [42; 43; 44]. Transplantation of pluripotent stem cell-derived retinal cells including RPE, PR, and RO into animal models of retinal degenerative diseases demonstrated their effectiveness in supporting visual function [45; 46; 47; 48; 49; 50; 51; 52].  
Clinical trials based on subretinal implantation of hESC-RPE and iPSC-RPE as a suspension in AMD and [PERSON]'s disease patients showed possible RPE engraftment without significant adverse events [7; 53]. There are at least three different clinical trials currently progressing at different centers but they are yet to publish results based on long-term assessments [54; 55; 56].  
Previous studies have shown that the transplantation of healthy photoreceptor precursors into the diseased retina improves visual function [57; 58; 59]. Initial investigators considered this as a result of the donor cell integration into the retina, but later studies proved that donor photoreceptors take part in a cytoplasmic exchange with the host photoreceptors instead of \"true integration\" [60; 61; 62]. Retinal progenitor cells (RPCs) found in the developing neural retina located in the inner layer of the optic cup are capable of differentiating into diverse retinal cell types. Human clinical trials conducted in patients with RP using fetal derived RPCs (fRPCs) demonstrated acceptable safety and tolerability of RPCs [63]. The results of two other clinical trials are on the way (NCT02464436, NCT03073733).  
Recent studies show that 3D retinal organoids (ROs) developed from iPSCs and ESCs can produce retinal progenitors that differentiate into RPE, PR, inner nuclear layer (INL) neurons, and ganglion cells (RGCs) [64; 65; 66; 67]. In preclinical studies, RO-derived retinal sheets formed structured outer nuclear layers (ONLs) with inner and outer segments [49; 51; 68]. Transplantation of PRs alone is also appealing but so far only a few protocols to produce PRs are suitable to use in clinical studies [69].  
Identifying the right disease stage for cell replacement is an important factor that determines the success of the therapy. In AMD, during the initial stages, only the BM and RPE are affected whereas the photoreceptors (PRs) remain preserved. In this scenario, only RPE replacement may be necessary to cure the disease condition. Combined BM-RPE-PR transplantation may be required for visual recovery in advanced stages of the diseases where the retina is irreversibly damaged (both PR and RPE are dysfunctional).