Introduction

Age-related macular degeneration (AMD), the main cause of central vision loss in patients older than 55Y worldwide, is initiated by the degeneration and loss of the retinal pigmented epithelium (RPE) in the macula caused by diverse mechanisms that remain under investigation [1, 2]. AMD is presented in two forms, neovascular (wet) and non-neovascular (dry). Existing therapies for wet AMD, including intravitreal injection of anti-VEGF (anti-vascular endothelial growth factor), photocoagulation, or both, show only limited effects in terms of both functional and anatomical improvement and just tend to stabilize the disease. On the other hand, dry AMD does not respond to current methods of therapy, and currently, no effective treatments can reverse it, although neuroprotective agents, visual cycle modulators [3], and drugs targeting the complement pathway are under investigation [4]. For many years, visual impairment due to retinal degeneration has been an incredible challenge for ophthalmologists and visual scientists who hope to restore this precious sense [5]. Over the past decade, tissue replacement approaches have given rise to the treatment of immedicable retinal diseases [6]. Stem cells, a nonspecialized immature cells without complex structures, have limitless self-renewal ability and are characterized by the power to differentiate into numerous types of cells in the body [7]. According to “Epigenetic Landscape” by Conrad Waddington [8], in 2006, Yamanaka’s team revolutionized the stem cell field by figuring out that somatic cells can be reprogrammed into embryonic stem cell (ESC)-like cells, called induced pluripotent stem cells (iPSCs) [9]. The possibility to produce patient-specific iPSCs provided a new horizon for both physicians and patients. Since iPSCs bypass many issues and ethics compared to ESCs [10], they show great promise as the main source for cutting-edge cell replacement therapy for different degenerative diseases, including AMD [11].

Technologies have made clinical-grade cell replacement therapies from pluripotent stem cells (both ESCs and iPSCs) possible for AMD. Stem cells can differentiate into bonafide-like RPE cells in vitro, albeit the derivation of RPE from iPSCs is a much faster and more cost-effective approach [1, 26]. With age, the permeability of the Bruch’s membrane structure changes and leads to the accumulation of N-retinylidene-N-retinylethanolamine (A2E) and lipofuscin, which are deposited between the Bruch’s membrane and RPE, leading to the formation of yellow drusen. The accumulation of drusen between the RPE and Bruch’s membrane inhibits metabolite transportation to the choroidal vessels and initiates inflammatory cascades. It is also highly phototoxic and has been linked to several oxidative changes, which, in turn, lead to damage or death of RPE and photoreceptors and further geographic atrophy and dysfunction of the Bruch’s membrane [28].

Fig. 1
figure 1

Schematic representation of retinal layers

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Current management of AMD

As discussed previously, there are two main categories for AMD: dry or non-neovascular AMD and wet or neovascular AMD. Currently, no effective treatment is available for dry AMD [19]. Although multiple targets such as complement inhibition, neuroprotection, and anti-inflammatory factors have been investigated for treatment of AMD, none have yielded positive results. These treatment failures can be justified by the concept of “the point of no return” in the disease cascade process which has led to irreversible cell loss (i.e., RPE and photoreceptors). The current clinical approach in the management of dry AMD is focused on dietary supplementation to prevent conversion to late stages of the disease without obvious visual benefit [29].

Available therapeutic options for wet AMD focus on limiting the neovascular membrane but do not repair the damage that may have already occurred. First-line therapy for patients who suffer from wet AMD is intravitreal VEGF inhibitors (e.g., ranibizumab, brolucizumab, bevacizumab, and aflibercept) [14].

Photodynamic therapy with/without anti-VEGF medications is another option for the treatment of patients where initial treatment with anti-VEGF was not effective. Thermal laser photocoagulation can result in enlarging scotoma or a new scotoma development, so it is rarely recommended nowadays [30].

Cell-based therapies for AMD

Cell therapy offers an unlimited source of cells for cell transplantation studies [31]. Currently, retinal cell transplantation, which is differentiated from various stem cells, is a hopeful therapeutic method in ophthalmology [31]. Several different cell types are presently under investigation for clinical cell therapy in AMD. Among all retinal cells, the most common target for cell therapy of AMD studies is the RPE cell [32]. One way of replenishing RPE cells in AMD involves delivering RPE cells to the subretinal space to restore physiological function to the tissue or organ. Retinal progenitor cell (RPC) and RPE produced from ESCs and iPSCs have been suggested as cell sources in preclinical and clinical trials [2, 24]. Stem cells are unspecialized cells of the human body. In addition to having the ability to differentiate into any cell of an organism, they can also self-renew. Pluripotent stem cells (PSCs) can form all germ layers but not extraembryonic structures, such as the placenta. Pluripotent stem cells include embryonic stem cells and induced pluripotent stem cells. Reprogramming of adult cells results in the production of induced pluripotent stem cells (iPSCs) [33, 34].

The use of the ESCs technique has been associated with ethical limitations and immunological complications upon allogeneic transplantation [35] when the origin of the donor cells is not from the recipient patient [36]. iPSCs technology by overcoming to ESC’s ethical challenges has been hailed as an effective replacement for ESCs and a prime candidate cell source for regenerative medicine aims. This technology opens new horizons for scientists in the area of regenerative medicine and cell therapy and provides encouraging results to replace damaged tissues in different pathologic processes [36].

iPSCs are induced reprogramming of differentiated somatic cells back into an embryonic-like pluripotent status. iPSCs technology was established by Shinya Yamanaka, who showed that ectopic expression of four pluripotency transcription factors, termed KLF4, c-MYC, OCT4 and, SOX2, could convert somatic cells to the pluripotent state, which can then be re-differentiated into various desired types of cells [37]. While iPSCs do not exist naturally, any healthy person or patient’s cells can be transformed into iPSCs in a healthy/patient-matched manner. iPSCs could provide an unlimited pool of autologous cells that can be used for transplants without the risk of immune rejection [19]. Easily accessible tissues, such as skin, blood and even urine can be used as a source of adult somatic cells for iPSCs derivation [38].

Retina has a complex architecture made up of the interconnection of a wide variety of cells [39]. Degenerative mechanisms that disrupt this interconnectivity can cause serious visual impairment in patients [40]; thus, future optimizing strategies that potentiate regeneration of the retina are necessary to prevent increases in the burden of retinal diseases [40]. Studies have demonstrated the low clinical efficiency of autologous RPE harvested from healthy locations of the patient’s retina [76]. To reduce any risk of gene alterations, DNA-free methods, using reprogramming proteins [77] or a combination of small chemical molecules [78], have been investigated to induced pluripotency in fibroblasts. In recent studies, the use of virus-free, xeno-free, c-MYC-free, and feeder-free methods has been adopted from published studies to develop a new protocol for clinical-grade iPSC from human cells [74]. Other concerns in the field of cell therapy are the possibility of genetic mutations leading to cancer, which may occur during the in vitro derivation of iPSCs [79].

Prior to clinical-grade use of iPSC and its derivations, it is necessary to check for cross-contamination of the cell lines [80].

Since stem cells cannot decontaminate themselves, their microbiological sterility is vital in order to prevent mycoplasma, bacterial, viral, and fungal contamination, which is evident in cell transplantation therapies [81]. A complete viral testing program is required for all human adventitious agents (e.g., HBV, HCV, HIV, and nucleic acid testing). As in most laboratories, iPSCs are created by reprogramming with viral factors; the remaining reprogramming vectors in the desired cells should also be checked to ensure the safety of the reprogrammed cells [82]. The viable cell count before transplantation is another important factor to consider, as well as testing its doubling time, as this provides information on genetic stability over time. It is also mandatory to immunostaining iPSCs or target cells with at least two specific markers [83].

It is crucial for clinical-grade iPSCs to have high efficacy during reprogramming. Studies demonstrate that small-molecule inhibitors (e.g., the P38 pathway, TGF-β receptor, inositol trisphosphate 3-kinase, and Aurora A kinase) can increase the efficacy of the reprogramming procedure significantly [42].

Conclusion

A multitude of therapeutic options based on stem cells has been explored over the last several decades. Since induced pluripotent stem cells (iPSCs) are less immunogenic and have less ethical controversy than hESC-based therapies, exploring their therapeutic potential is particularly intriguing. iPSC-derived RPE transplants became available novel treatment to humans after a decade of preclinical studies to restore vision for the patient who suffers from AMD. There has been enough evidence produced so far to confirm the safety of these potential therapeutic approaches in phase I/II clinical trials. Thus, there is probably less time to go until we have a stem cell-based treatment for acute wet AMD since only RPE cells with Bruch's membrane need replacing. However, we are far from being able to treat late dry AMD because the chronic loss of RPE will also result in secondary loss of photoreceptors overlying the affected retina. As discussed in this review, further studies must take advantage of the manufacturing process and subretinal delivery of the transplanted cell to improve the efficacy of RPE fabrication and their integration into the retina as well as improve the retina microenvironment for long-term integration and survival of transplanted cells.