Introduction

The macula luteal (an oval-formed pigmented zone near the center of the eye retina) can participate in the central, high-resolution, and color vision. Macular degeneration is a disorder in which macula luteal deteriorates and results in the reduction or loss of central visual acuity. Different types of macular degeneration are including age-related macular degeneration (AMD), juvenile macular degeneration, and Stargardt’s disease (Bressler et al. 1988; Nowak 2006; de Jong et al. 2020). While a group of conditions can lead to macular degeneration, aging is the most common causes. Accordingly, AMD is a serious threat to the vision of older than 50 years of subjects (Veritti et al. 2012). Therefore, the evaluation of appropriate approaches to early diagnose and treatment is very worthwhile. In recent decades, the rationale of cell therapy and regenerative medicine for promoting tissue repair and treatment of different disease including AMD has been proven(Goodarzi et al. 2014, 2015; Soleimani et al. 2016, Goodarzi et al. 2018, Singh and MacLaren 2018; Waugh et al. 2018; Goodarzi et al. 2019; Larijani, Goodarzi et al. 2019). However, many uncertainties in conducting clinical trials such as the most suitable route and dosage of administration have existed. Herein, some preclinical investigations have also been prepared on the therapeutic application of stem cells (Djulbegovic 2007; Parekkadan and Milwid 2010; Isasi et al. 2016; Krause et al. 2019). For preclinical investigations, selection of the appropriate animal model and performing detailed molecular tests are necessary (Council 2006; Denayer et al. 2014; Goodarzi et al. 2019; Larijani et al. 2019). On the other hand, it is helpful to evaluate the mechanism of disease to prepare detailed molecular tests (Darbre and Darbre 1988). Since, current review aims to summarize the points about the AMD and its mechanisms along with consideration of the cell therapy importance through the evaluation of pre-clinical and clinical studies.

Age-related macular degeneration: symptoms, causes, and treatments

AMD as the common cause of poor vision in the elderly people of the industrialized countries is a multifactorial late-onset disorder (Swaroop et al. 2009; Villegas et al. 2017). Although the etiology of AMD is unknown, combination of hereditary (such as specific gene polymorphisms, lighter eye color and etc.) and non-hereditary factors (including over-exposure to sunlight, life style, drug side effects, aging and etc.) are considered as AMD risk factors. With regards to the growing old population in most part of the world, it is expected that the number of AMDs will be increased in the coming years. In this regard, a study has predicted the prevalence of AMDs will be reached to 196 million and 11 million of them will have severe visual difficulties by 2020 (Moore et al. 2017).

Two forms of macular degeneration are recognized: dry (non-neovascular) and wet (neovascular). While the wet form is more serious, fortunately the dry form is more common (Hussain and Ciulla 2017). Pathophysiology of dry (or geographic atrophy) form is reducing blood supply to macula which can be diagnosed by drusen deposits in and around the macula (Moore et al. 2017). Hereupon, abnormal overgrowth of choroidal blood vessels beneath the retina leads to the wet form of macular degeneration. Studies have shown the abnormal presence of vascular endothelial growth factor (VEGF) has more prominent role in vascular overgrowth than other factors such as angiopoietin, endothelin, and activin in the wet form (Semeraro et al. 2013; Campochiaro et al. 2016). While the available treatment agents for dry form are only preventive, the wet form has the food and drug administration (FDA)-approved treatments. Subsequently, anti-VEGF agents are the most common treatments of neovascularization form of macular degeneration (Table 1). Despite the various available treatments, presence of several complications such as different alternative angiogenic factors and pathways, local and systemic side effects of anti-VEGF intra-ocular injections, tolerance to common drugs in some patients, and financial difficulties lead to the need of new methods and treatments (Cabral et al. 2017; Hussain and Ciulla 2017). Recently, stem cell therapy as a pioneering method in regenerative medicine develops a promising therapeutics for disorders including macular degeneration (Goodarzi et al. 2019).

Table 1 various treatments are suggested for macular degeneration and some of these treatments are FDA-approved while some others are on the way of getting the FDA approval
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Mechanisms of age: related macular degeneration

AMD is known as a multifactorial disease in which multiple environmental, biological, and genetic factors are involved (Fig. 1). Better understanding of these risk factors and their mechanisms will help to develop novel effective treatment regimens.

Fig. 1
figure 1

AMD is a multifactorial disorder. Various hereditary and non-hereditary factors play role in pathophysiology of AMD (Seddon et al. 2010; Chen et al. 2011; Sharma et al. 2014). AMD: Age-related macular degeneration

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Environmental factors

AMD is associated with different environmental risk factors including smoking (one of the strong risk factors as known inducer of oxidative stress), life style, diet include low omega3 fatty acids and antioxidants such as lutein and zeaxanthin, heavy alcohol intake, increase body mass index (BMI), over exposure to sunlight, increase the occurrence risk of AMD (Allikmets et al. 1997; Chong et al. 2008; Cano et al. 2010; Huang et al. 2014). There are evidences of association between hypertension and cardiovascular disease and AMD (Al-Zamil and Yassin 2017). However, more investigations are required to elucidate these and other new risk factors.

Cellular and molecular factors

Aging as a biological process affects the cells through different ways and these cellular and molecular alterations lead to age-related diseases such as AMD (Larijani et al. 2019). Studies have shown the accumulation of cholesterol, lipofuscin, and drusen deposits in various ocular layers increases as individuals get older. Subsequently, disordered protein metabolism, mitochondrial dysfunction and A2E increase in lipofuscins in aging process impair the normal apoptosis and activate the inflammatory response (Swaroop et al. 2009). In this regard, Ambati et al. has been reported that the mice deficient in monocyte chemoattractant protein-2 (CCL-2) and C–C chemokine receptor-2 (CCR-2) have shown some AMD characteristics through macrophage dysfunction which leads to accumulation the lipofuscin and drusen in the retina (Ambati et al. 2003). Generally, the different genetic variants are related to AMD. Among different relevant genes association of the complement factor H (CFH), CFB, and ARMS2/HTRA1 variants are more investigated. (Swaroop et al. 2009). Also, hepatic lipase (LIPC) is one of the main enzymes in the metabolism of triglycerides which its gene variants association with AMD has been studied (Seddon et al. 2010). A body of literatures have reported the relation between the increased levels of tissue inhibitor of metalloproeinase-3 (TIMP-3) and Immediate Early Response-3 (IER-3) and AMD (Vazquez-Chona et al. 2005; Strunnikova et al. 2010; Anand et al. 2016). Although there are other new unknown molecules and genes that further studies will indicate.

The importance of cell therapy in age: related macular degeneration treatment

Nowadays, new advancements in medicine especially breakthroughs in cell therapy help optimize the treatments of incurable diseases such as Parkinson, Alzheimer, and AMD (Goodarzi et al. 2019; Larijani et al. 2019). According to the ability of self-renewal and differentiation potential toward multiple lineages stem cells become a promising therapeutic choice in cell therapy. Various types of stem cells including embryonic stem cells (ESCs), adult stem cells, and induced Pluripotent Stem Cells (iPSCs) are identified (Öner 2018). Retinal cell transplantation as a promising therapeutic method in ophthalmology benefit a lot from stem cells. Herein, cell therapy provides limitless source of undifferentiated cells for cell transplantation. Furthermore, mesenchymal stem cells (MSCs) derived from different sources such as bone marrow and adipose tissue, ESCs, and iPSCs are the common studied stem cells in retinal degenerative diseases (Siqueira 2011; Guan et al. 2013; Sugitani et al. 2013; He et al. 2014; Tsuruma et al. 2014; Jian et al. 2015). Though some of these stem cells are more studied in macular cell therapies and they will be discussed subsequently.

Gold standard cell type for treatment of age: related macular degeneration

Retinal pigment epithelium (RPE) cells as the most common target of cell therapy is one type of the cells damaged in retinal degenerative diseases. Different stem cells transplantation which differentiated into the RPE cells are studied in preclinical and clinical trials (Fox et al. 2014; Zarbin et al. 2019). Though, nowadays RPE and retinal progenitor cell (RPC) derived from ESCs and PSCs become the favorite sources for retinal cell therapy (Stern and Temple 2011; Buchholz et al. 2013; Leach and Clegg 2015; Nazari et al. 2015). Preclinical and clinical studies are applied these stem cells derived from various methods, with different cell amounts, and route of delivery.

Animal models for cell therapy in age: related macular degeneration

Until now, different animal models have been designed based on AMD genetic and environmental causative factors which can mimic the pathological features of disease. But generally, designing and selecting the most appropriate model for AMD is challenging because of the complexity of these factors (Zeiss 2010). Hereupon, the most appropriate animal model is an inexpensive, accessible model which is able to exhibit histological and functional changes and has a short-term growth and developmental period (Held 1983; Rabadán-Diehl and Nathanielsz 2013; Goodarzi et al. 2019). Accordingly, different animal models were used for AMD (Table 2).

Table 2 Animal models of age-related macular degeneration
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Clinical trials

As discussed above, different stem cell sources are studied in vitro and in vivo in retinal degenerative disorders. However, clinical studies are demanded to translate the preclinical breakthrough into clinics. In this regard, some clinical trials are conducted to investigate the effectiveness of the cell therapy for ocular diseases. Two phase I/II, open-label, and nonrandomized clinical trials have shown the safety, tolerability, and efficacy of the Human Embryonic Stem Cell Derived Retinal Pigmented Epithelial (hESC-RPE) cells in patients with Stargardt’s Macular Dystrophy (SMD) and advanced dry AMD respectively in the United Kingdom and U.S. Accordingly, other trials are ongoing in transplantation of hESC-RPE cells in such cases (Schwartz et al. 2015; Schwartz et al. 2016; da Cruz et al. 2018). Also, there are some registered clinical trials in using MSCs derived from bone marrow and umbilical cord in treating the AMD or retinitis pigmentosa (RP). Another clinical trial in the United States has used an encapsulated RPE cell line in AMD or RP and Usher Syndrome patients. Results have shown the efficacy of the secreting neurotrophic factors from these cell lines for preservation (Jones et al. 2017). In addition, telomerase-mediated cell and gene therapy have been reviewed for the prevention of the RPE cell function devaluation during aging (Rowe-Rendleman and Glickman 2004; Immonen et al. 2009; Liu et al. 2019). However, still there is no FDA-approved stem cell therapy for macular degeneration and further trials and studies are required.

Route of cell administration

There are two common cellular delivery systems in retinal cell therapy: cell suspension and cellular sheets. Cell suspension including seeded cells on special substrates which inserted into the eye. In the second method, scaffolds provide a monolayer cell sheets implanted in the eye. Hu, Liu et al. has carried out an animal study to discuss the privilege of the second method. The scaffolds of the second method provide the cellular viability and stability, efficient cellular function and differentiation regulation, less migratory possibility, and effective cellular transplantation. (Lu et al. 2001; Schwartz et al. 2012; Aziz et al. 2019).

Conclusion and the future emerging landscape

Due to the emotional and economic burden of AMD along with the potential dangers related to vision problems, stem cell-based therapies considered as a very promising treatment approach. Accordingly, multiple types of stem cells were investigated to regenerate atrophic or damaged retinal tissue. However, applying stem cell-based therapeutic products are still needed preclinical investigations to support their innovative therapeutic effects (MacPherson and Kimmelman 2019; Riva and Petrini 2019). Indeed, preclinical studies can help to select the appropriate cell type, dosage, and administration methods for treatment. One of the most common parts of the preclinical studies involves the use of animal models. Considering that the use of animals in scientific research is highly controversial, it is better to use alternative methods based on the 3Rs (Replacement, Reduction, and Refinement) principles including the novel in vitro and computational in silico methods(Goodarzi et al. 2019; Hubrecht and Carter 2019; Larijani et al. 2019). On the other hand, the systemic biology approaches can be used for developing modern treatments designed for prevention(Schleidgen et al. 2017) and helping the AMD cure by evaluating AMD underlying mechanisms. It is generally hoped that all of these approaches will be effective in the road of treatment.