Stem cell therapy for retinal diseases: update
Stem Cell Research & Therapy volume 2, Article number: 50 (2011)
Distinct stem cell types have been established from embryos and identified in the fetal tissues and umbilical cord blood as well as in specific niches in many adult mammalian tissues and organs such as bone marrow, brain, skin, eyes, heart, kidneys, lungs, gastrointestinal tract, pancreas, liver, breast, ovaries, and prostate. All stem cells are undifferentiated cells that exhibit unlimited self-renewal and can generate multiple cell lineages or more restricted progenitor populations that can contribute to tissue homeostasis by replenishing the cells or to tissue regeneration after injury. The remarkable progress of regenerative medicine in the last few years indicates promise for the use of stem cells in the treatment of ophthalmic disorders. Experimental and human studies with intravitreal bone marrow-derived stem cells have begun. This paper reviews recent advances and potential sources of stem cells for cell therapy in retinal diseases.
Stem cell (SC) therapy is not a new concept. In the after-math of the bombings of Hiroshima and Nagasaki in 1945, researchers discovered that bone marrow (BM) transplanted into irradiated mice produced hematopoiesis . Hematopoietic stem cells (HSCs) were first identified in 1961, and their ability to migrate and differentiate into multiple cell types was documented .
Distinct SC types have been established from embryos and identified in fetal tissues and umbilical cord blood (UCB) as well as in specific niches in many adult mammalian tissues and organs such as BM, brain, skin, eyes, heart, kidneys, lungs, gastrointestinal tract, pancreas, liver, breast, ovaries, prostate, and testis . All SCs are undifferentiated cells that exhibit unlimited self-renewal and can generate multiple cell lineages or more restricted progenitor populations that can contribute to tissue homeostasis by replenishing the cells or to tissue regeneration after injury [4, 5].
A progenitor cell is a biological cell that, like an SC, has a tendency to differentiate into a specific type of cell but is already more specific than an SC and is pushed to differentiate into its 'target' cell. The most important difference between SCs and progenitor cells is that SCs can replicate indefinitely, whereas progenitor cells can divide only a limited number of times. Controversy about the exact definition remains and the concept is still evolving.
Several investigations [5–7] have been carried out with isolated embryonic, fetal, and adult SCs in a well-defined culture microenvironment to define the sequential steps and intracellular pathways that are involved in their differentiation into the specific cell lineages. More particularly, different methods, including the use of cell feeder layers, cell-free conditions, and extracellular matrix molecules such as collagen, gelatin, and laminin and diverse growth factors and cytokines, have been developed for the in vitro culture of SCs [3, 5].
Age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy are the three most common causes of visual impairment and legal blindness in developed countries [8–10]. One common denominator of these conditions is progressive loss of the neural cells of the eye - photoreceptors, interneurons, and retinal ganglion cells, or RGCs - and essential supporting cells such as the retinal pigment epithelium (RPE). Retinal dystrophies - retinitis pigmentosa (RP) (Figure 1), Stargardt disease, Best disease, Leber congenital amaurosis, and so on - all evolve with early loss of photoreceptors and subsequent loss of RGC. Recent years have seen enormous progress in the treatment options that stop the progression of AMD from a neovascular state to fibrosis, that slow down the progression of glaucoma by reducing intraocular pressure, and that prevent progression of diabetic retinopathy by optimizing glycemic control and treat retinal neovascularization early [11–14]. However, irreversible visual loss still occurs in a significant proportion of cases. Research is aimed at developing novel treatments using neuroprotective and regenerative strategies.
SCs can potentially be used for both neuroprotection and cell replacement. Intravitreal delivery of neurotrophic factors slows down photoreceptor degeneration in rodent models of RP, RGC loss in glaucoma models, and optic nerve and optic tract trauma, but the effect may be temporary. Slow-release preparations and gene therapy approaches used to induce retinal cells to secrete neurotrophic factors are two ways to induce longer-term effects. A third option is to use SCs as long-term delivery agents, possibly encapsulated in a device, because many SCs either secrete neurotrophins naturally or can be genetically engineered to do so [15–17]. SCs can be injected into the eye through the intravitreal or subretinal technique [18–21].
Progress has also been made in the field of photo-receptor, RPE, and RGC replacement by SCs and progenitor cells, although long-term restoration of visual function has not been confirmed. The recent discoveries that human fibroblasts can be 'reprogrammed' to behave like embryonic SCs and that adult eyes harbor retinal progenitor cells (RPCs) also increase the potential availability of SCs for transplantation, including autologous transplantation, and stimulate intrinsic 'self-regeneration', which could potentially overcome a lot of the problems associated with non-autologous transplantation in humans .
Potential sources of stem cells for cell therapy in retinal diseases
Bone marrow-derived stem cells
BM-derived SCs have been proposed as a potential source of cells for regenerative medicine [9, 22]. This is based on the assumption that HSCs isolated from BM are plastic and are able to 'transdifferentiate' into tissuecommitted SCs for other organs (for example, heart, liver, or brain). Unfortunately, the concept of SC plasticity was not confirmed in recent studies, and previously encouraging data demonstrating this phenomenon in vitro could be explained by a phenomenon of cell fusion or, as believed by our group, by the presence of heterogeneous populations of SCs in BM . The identification of very small, embryonic-like SCs in BM supports the notion that this tissue contains a population of primitive SCs, which, if transplanted together with HSCs, would be able to regenerate damaged tissues in certain experimental settings. Cells from BM are easily and safely aspirated. After administration of local anesthesia, about 10 mL of the BM is aspirated from the iliac crest by means of a sterile BM aspiration needle; subsequently, mononuclear BM-derived SCs are separated by using the Ficoll density separation method [3, 18].
SC-based therapy has been tested in animal models for several diseases, including neurodegenerative disorders such as Parkinson disease, spinal cord injury, and multiple sclerosis. The replacement of lost neurons that are not physiologically replaced is pivotal for therapeutic success. In the eye, degeneration of neural cells in the retina is a hallmark of widespread ocular diseases such as AMD and RP. In these cases, the photoreceptor loss that occurs as a primary event (as in RP) or secondary to loss of RPE (as in AMD) leads to blindness [3, 9].
BM is an ideal tissue for studying SCs because of its accessibility and because proliferative dose responses of BM-derived SCs can be readily investigated. Furthermore, there are a number of well-defined mouse models and cell surface markers that allow effective studies of hematopoiesis in healthy and injured mice. Because of these characteristics and the experience of BM transplantation in the treatment of hematological cancers, BM-derived SCs have also become an important tool in regenerative medicine. The BM harbors at least two distinct SC populations: HSCs and mesenchymal stem cells (MSCs) [24, 25].
Hematopoietic stem cells
HSCs are multipotent SCs that give rise to all of the blood cell types, including myeloid lineages (monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, and dendritic cells) and lymphoid lineages (T cells, B cells, and natural killer cells). HSCs are found in adult BM in, for example, femurs, hips, ribs, the sternum, and other bones. Cells can be obtained directly from the hip by using a needle and syringe (Figure 1) or from the blood after pretreatment with cytokines, such as G-CSFs (granulocyte colony-stimulating factors), that induce cells to be released from the BM compartment. Other sources for clinical and scientific use include UCB and placenta [23, 24].
In reference to phenotype, HSCs are identified by their small size, lack of lineage markers, low staining (side population) by vital dyes such as rhodamine 123 (rhodamine-dull, also called rholo) or Hoechst 33342, and presence of various surface antigenic markers, many of which belong to the cluster of differentiation (CD) series (CD34, CD38, CD90, CD133, CD105, and CD45) and also c-kit and SC factor receptor [26–31]. Otani and colleagues  demonstrated that, whenever a fraction of mouse or human adult BM-derived SCs (lineage-negative hematopoietic stem cells, or Lin-HSCs) containing endothelial precursors stabilizes and rescues retinal blood vessels that would ordinarily completely degenerate, a dramatic neurotrophic rescue effect is also observed. Retinal nuclear layers are preserved in two mouse models of retinal degeneration, rd1 and rd10, and detectable, albeit severely abnormal, electroretinogram recordings are observed in rescued mice at times when they are never observed in control-treated or untreated eyes. The normal mouse retina consists predominantly of rods, but the rescued cells after treatment with Lin-HSCs are nearly all cones. Microarray analysis of rescued retinas demonstrates significant upregulation of many anti-apoptotic genes, including small heat shock proteins and transcription factors.
Some reports have demonstrated the clinical feasibility of the intravitreal administration of autologous bone marrow-derived mononuclear cells (ABMCs) in patients with advanced degenerative retinopathies [32, 33]. More recently, our group conducted a prospective, phase I, non-randomized, open-label study that included three patients with RP and two patients with cone-rod dystrophy and an Early Treatment Diabetic Retinopathy Study best-corrected visual acuity of 20/200 or worse . Evaluations such as best-corrected visual acuity, full-field electroretinography, kinetic visual field (Goldman), fluorescein and indocyanine green angiography, and optical coherence tomography were performed at baseline and 1, 7, 13, 18, 22, and 40 weeks after intravitreal injection of 10 × 106 ABMCs (0.1 mL) into one study eye of each patient. No adverse event associated with the injection was observed. A 1-line improvement in best-corrected visual acuity was measured in four patients 1 week after injection and was maintained throughout follow-up. Three patients showed undetectable electroretinography responses at all study visits, whereas one patient demonstrated residual responses for darkadapted standard flash stimulus (a wave amplitude of approximately 35 mV), which remained recordable throughout follow-up, and one patient showed a small response (a wave amplitude of approximately 20 mV) recordable only at weeks 7, 13, 22, and 40. Visual fields showed no reduction (with a Goldman Standard V5e stimulus) for any patient at any visit. No other changes were observed on optical coherence tomography or fluorescein and indocyanine green angiograms. We conclude that intravitreal injection of ABMCs in eyes with advanced RP or cone-rod dystrophy was associated with no detectable structural or functional toxicity over a period of 10 months .
Mesenchymal stem cells
MSCs are progenitors of all connective tissue cells. In adults of multiple vertebrate species, MSCs have been isolated from BM and other tissues, expanded in culture, and differentiated into several tissue-forming cells such as bone, cartilage, fat, muscle, tendon, liver, kidney, heart, and even brain cells.
According to the International Society for Cellular Therapy , there are three minimum requirements for a population of cells to be classified as MSCs. The first is that MSCs, unlike BM-derived hematopoietic cells, are isolated from a population of mononuclear cells on the basis of their selective adherence to the surface of the plastic of culture dishes; a disadvantage of this method of identification is the possible contamination by hematopoietic cells and cellular heterogeneity with respect to the potential for differentiation. Second, CD105, CD73, and CD90 must be present and CD34, CD45, CD14 or CD11b, CD79, or CD19 and HLA-DR must not be expressed in more than 95% of the cells in culture. Finally, the cells can be differentiated into bone, fat, and cartilage .
A number of studies have shown that BM-derived MSCs can differentiate into cells expressing photoreceptor proteins when injected into the subretinal space [37, 38]. Interestingly, it has been suggested that rat MSCs can be made to express photopigment (rhodopsin) in vitro simply by adding epidermal growth factor to the culture media . Additionally, although other retinarelevant cell types have been engineered, a number of studies have shown that BM- or adipose tissue-derived MSCs are converted to RPE cells [39–41]. As with work on other neuronal phenotypes, however, there has now been a reassessment of the ability of MSCs to differentiate into functionally useful retinal cells. Some studies have shown that transplanted BM-derived MSCs do not differentiate into neural retinal cells . In an in vitro rat retina-explant model, untreated MSCs seemed to transdifferentiate into microglia109 in a way reminiscent of earlier work on MSC transplants in other neurological tissue . Some limited improvement was seen with pre-treatment with brain-derived neurotrophic factor (BDNF), nerve growth factor, and basic fibroblast growth factor (bFGF) in terms of morphological differentiation into retinal neurons and expression of NF200, GFAP, PKC-alpha, and recoverin, but these cells did not express rhodopsin .
In an ischemic retina rodent model, MSCs injected into the vitreous cavity have been shown to mature (with expression of neuron-specific enolase and neurofilament) and secrete ciliary neurotrophic factor (CNTF), bFGF, and BDNF for at least 4 weeks . Animal studies have also demonstrated that subretinal transplantation of MSCs delays retinal degeneration and preserves retinal function through a trophic response . UCB-derived MSCs have also been shown to be neuroprotective of rat ganglion cells . Very recently, the intravenous administration of BM-derived MSCs was shown to prevent photoreceptor loss and preserve visual function in the Royal College of Surgeons (RCS) rat model of RP .
A role for genetically modified MSCs may emerge in the treatment of subretinal neovascularization. It has been shown that BM-derived MSCs accumulate around subretinal membranes induced by retinal laser burns. Intravenous injection of mouse BM-derived MSCs genetically engineered to secrete pigment epithelium-derived factor resulted in smaller neovascular complexes .
Induced pluripotent stem cells
Current methods of producing SCs from adult somatic cells offer an alternative cell source for transplantation. Induced pluripotent stem cells (iPSCs) are morphologically identical to embryonic SCs, display similar gene expression profiles and epigenetic status, and have the potential to form any cell in the body [45, 50]. These cells have been employed to generate cells for the treatment of various diseases, including diabetes, cardiovascular disease, sickle cell anemia, Parkinson disease, and hemophilia [51–55]. Meyer and colleagues  recently showed that iPSCs can differentiate into retinal cell types, whereas a paper by Buchholz and colleagues  showed that human iPSCs can be differentiated into retinal pigment epithelial cells that display functionality in vitro.
Carr and colleagues  demonstrated that iPSCs can be differentiated into functional iPSC RPE cells and that transplantation of these cells can facilitate the short-term maintenance of photoreceptors through phagocytosis of photoreceptor outer segments. Long-term visual function is maintained in this model of retinal disease even though the xenografted cells are eventually lost, suggesting a secondary protective host cellular response. Zhao and colleagues  showed that abnormal gene expression in some cells differentiated from iPSCs can induce T cell-dependent immune response in syngeneic recipients. Therefore, the immunogenicity of therapeutically valuable cells derived from patient-specific iPSCs should be evaluated before any clinical application of these autologous cells into the patients.
Owing to viral insertions of pluripotency genes, this particular line of iPSC RPE cells cannot be used as a direct therapy, but recent advances in iPSC cell reprogramming technology, including the use of small molecules , piggyBac transposition [61, 62], nonintegrating episomal vectors , and manipulation of endogenous transcription factors , should eliminate the risks associated with the integration of SC genes into the genome. Furthermore, the finding that blood cells can be used to derive iPSCs  may remove the need for the invasive biopsies required to collect somatic cells and accelerate the ethical production of SC-derived tissue for therapeutic use.
Human embryonic stem cells
The human embryonic stem cell (hESC) is defined as a cell that can both renew itself by repeated division and differentiate into any one of the 200 or more adult cell types in the human body. An hESC arises from the eightcell stage morula. Outside of normal development, hESCs have been differentiated in vitro into neural cell types and even pigmented epithelium, although controlling their differentiation has proven challenging. Several hESC lines exist and are supported by public research funds. The use of hESCs has significant limitations, including ethical issues, and a risk of teratoma formation, but the chief problem is that we are still struggling to understand the developmental cues that differentiate hESCs into the specific adult cell types required to repair damaged tissues .
Nistor and colleagues  showed, for the first time, that three-dimensional early retinal progenitor tissue constructs can be derived from hESCs. Three-dimensional tissue constructs were developed by culturing hESC-derived neural retinal progenitors in a matrix on top of hESC-derived RPE cells in a cell culture insert. An osmolarity gradient maintained the nutrition of the three-dimensional cell constructs. Cross-sections through hESC-derived tissue constructs were characterized by immunohistochemistry for various transcription factors and cell markers. Tissue constructs derived from hESCs expressed transcription factors characteristic of retinal development, such as pax6, Otx2, Chx10, retinal RAX, Brn3b (necessary for differentiation of RGCs), and crx and nrl (which have a role in photoreceptor development). Many cells expressed neuronal markers, including nestin, beta-tubulin, and microtubule-associated protein.
Assessments of safety and efficacy are crucial before hESC therapies can move into the clinic. Two important early potential hESC applications are the use of RPE cells for the treatment of AMD and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Long-term safety and function of RPE from hESCs in preclinical models of macular degeneration were demonstrated by Lu and colleagues . They showed long-term functional rescue by using hESC-derived RPE in both RCS rats and Elov14 mice, which are animal models of retinal degeneration and Stargardt disease, respectively. Good manufacturing practice-compliant hESC RPE cells survived subretinal transplantation in RCS rats for prolonged periods (>220 days). The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions.
Near-normal functional measurements were recorded at survival of greater than 60 days in RCS rats. To further address safety concerns, a good laboratory practice-compliant study was carried out in the NIH III immunedeficient mouse model. Long-term data (spanning the life of the animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal hESC RPE cell transplantation. These results suggest that hESCs could serve as a potentially safe and inexhaustible source of RPE cells for the efficacious treatment of a range of retinal degenerative diseases.
In 2010, the US Food and Drug Administration granted orphan drug designation to RPE cells for Advanced Cell Technology, Inc. (Santa Monica, CA, USA) to initiate its phase 1/2 clinical trials using RPE cells derived from hESCs to treat patients with Stargardt macular dystrophy. Moreover, in 2011, the company received a positive opinion from the Committee for Orphan Medicinal Products of the European Medicines Agency for the designation of this product as an orphan medicinal product for the treatment of Stargardt disease [69, 70].
Retinal progenitor cells
RPCs, considered the active cellular component of fetal retinal transplants, were purified from green fluorescent protein transgenic mice and transplanted into the degenerating retina of a mature mouse model. The transplanted RPCs developed into neurons, including presumptive photoreceptor cells expressing rhodopsin, opsin, and recoverin. The host showed rescue of the outer retina layer cells with integration of donor cells occurring in multiple retinal layers. The greatest concentration of integration in the outer retina and, most importantly, recipient mice, demonstrated an improved response to light [71, 72].
In adults, the neural retina and RPE have overlapping regenerative capacity after injury (for example, in amphibians, injury can activate both retinal and RPE progenitor cells to mediate regeneration and repair). Limited damage of amphibian retina activates progenitor cells within the neural retina, presumably retina stem cells (RSCs), to mediate regeneration and repair, whereas extensive damage that destroys most of the neural retina results in the activation of a progenitor cell population within the RPE layer, presumably retinal pigment epithelial SCs, to regenerate both neural retina and RPE [72, 73]. RSCs have been isolated from the edge of the peripheral region of the neurosensory mammalian retina, although questions regarding the true origin of these cells and the ability to self-renew have been raised [74, 75].
More recently, RSCs that demonstrate self-renewal and differentiated progeny have been isolated from the posterior neural retina. Of the multiple types of RSCs and RPCs reported, retinal glial Müller cells are the most studied late progenitors that retain competency to produce neuronal lineages, including photoreceptor cells. Müller glial cells actively regenerate damaged retina in lower animals and can be similarly activated in mice by application of growth factors. Although the Müller cells reside in the retina and have properties of RSCs, they also produce all major neural lineages, in which there are multipotent neural SCs [72, 76–79].
Endothelial progenitor cells
Endothelial progenitor cells (EPCs) are a minor population of mononuclear cells circulating in peripheral blood. Though rare in comparison with other blood cells, EPCs are capable of facilitating vascular repair in different ischemic tissues; therefore, EPCs have been regarded as promising candidates for inducing therapeutic angiogenesis in multiple diseases such as acute myocardial infarction, unstable angina, stroke, diabetic microvasculopathies, pulmonary arterial hypertension, atherosclerosis, and ischemic retinopathies [80, 81].
Numerous studies suggest that EPCs re-vascularize ischemic tissues, and recent clinical trials have highlighted the feasibility, safety, and potential therapeutic benefit of an EPC-based cytotherapy for myocardial infarction. However, there are still discrepancies about the extent to which these cells incorporate into the vasculature and the level to which they restore functionality to damaged tissue. These controversies are caused by an imprecise EPC definition as many different cell populations are collectively referred to as EPCs. Recently, Medina and colleagues  described a distinct EPC population named outgrowth endothelial cells (OECs). OECs were isolated from adult human peripheral blood and grown on collagen substrate. OECs were able to closely interact with mature endothelial cells through adherens and tight junctions. OECs demonstrated de novo tubulogenic potential and fully incorporate into a mature vascular network. This is also demonstrated in vivo, where OECs directly incorporate into resident ischemic vasculature and significantly decreased avascular areas (P < 0.001) when compared with vehicle-injected retinas. The authors concluded that OECs have great potential as an alternative treatment for ischemic retinopathies .
Possible mechanisms of retinal function recovery with the use of cell therapy (paracrine effect)
SCs may be able to restore the functioning of the retina through two paths: cell replacement (described above with the different types of SC) and rescue therapy (the paracrine effect). The paracrine effect is defined as an action exerted by a substance secreted by a cell on local cellular environments. Some cell-to-cell communication requires direct cell-to-cell contact. Some cells can form gap junctions that connect their cytoplasm to the cytoplasm of adjacent cells. In cardiac muscle, gap junctions between adjacent cells allow action potential propagation from the cardiac pacemaker region of the heart to spread and coordinately cause contraction of the heart.
SCs transplanted into injured tissue express paracrine signaling factors, including cytokines, chemokines, and growth factors, which are involved in orchestrating the SC-driven repair process. However, our understanding of the mechanistic basis for SC-mediated paracrine enhancement of end-organ function remains incomplete. The paracrine effect can be divided into several mechanisms and may benefit the treatment of retinal diseases, helping to improve the functioning of cells, as described in Table 1[3, 26, 39, 83–87].
Routes of stem cell transplantation for retinal diseases
Routes that were tested for cell therapy for retinal diseases are systemic administration (intravenous), intravitreal injection, and subretinal injection (Figure 1). Figure 2 shows the two subretinal injection techniques: (A) injection of cell suspensions and (B) injection of cells adhered to a matrix (scaffold) [20, 88–90].
SCs maintain the balance between somatic cell populations in various tissues and are responsible for organ regeneration. The remarkable progress of regenerative medicine in the last few years indicates promise for the use of SCs in the treatment of ophthalmic disorders. Based on the abovementioned mechanisms, experimental and human studies with intravitreal BM-derived SCs have begun (Table 2) [91, 92]. History is starting to be written in this very promising therapeutic field.
autologous bone marrow-derived mononuclear cell
age-related macular degeneration
brain-derived neurotrophic factor
basic fibroblast growth factor
endothelial progenitor cell
human embryonic stem cell
hematopoietic stem cell
induced pluripotent stem cell
lineage-negative hematopoietic stem cell
mesenchymal stem cell
outgrowth endothelial cell
Royal College of Surgeons
retinal ganglion cell
retinal progenitor cell
retinal pigment epithelium
retina stem cell
umbilical cord blood.
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Advanced Cell Technology, Inc. homepage. [http://www.advancedcell.com]
I thank Júlio Cesar Voltarelli, André Marcio Vieira Messias, and Rodrigo Jorge, who are medical researchers at the University of São Paulo (Ribeirão Preto, São Paulo, Brazil) and who are participating in the clinical study of stem cells for treatment of retinitis pigmentosa.
The author declares that they have no competing interests.
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Siqueira, R.C. Stem cell therapy for retinal diseases: update. Stem Cell Res Ther 2, 50 (2011). https://doi.org/10.1186/scrt91
- Retinal Pigment Epithelium
- Retinal Pigment Epithelium Cell
- Retinitis Pigmentosa
- Neural Retina
- Orphan Medicinal Product