Diabetic Retinopathy and Stem Cell Therapy

*Sevil Kestane*

## **Abstract**

This overview was evaluated by the development of diabetic retinopathy (DR) and the stem cell therapy approach. DR is a microvascular complication of diabetes mellitus, characterized by damage to the retinal blood vessels leading to progressive loss of vision. However, the pathophysiological mechanisms are complicated and not completely understood yet. The current treatment strategies have included medical, laser, intravitreal, and surgical approaches. It is known that the use of mesenchymal stem cells (MSC), which has a great potential, is promising for the treatment of many degenerative disorders, including the eye. In retinal degenerative diseases, MSCs were ameliorated retinal neurons and retinal pigmented epithelial cells in both *in vitro* and *in vivo* studies. Stem cell therapies show promise in neurodegenerative diseases. However, it is very important to know which type of stem cell will be used in which situations, the amount of stem cells to be applied, the method of application, and its physiological/neurophysiological effects. Therefore, it is of great importance to evaluate this subject physiologically. After stem cell application, its safety and efficacy should be followed for a long time. In the near future, widespread application of regenerative stem cell therapy may be a standard treatment in DR.

**Keywords:** diabetic retinopathy, mesenchymal stem cells, cell therapy, regenerative stem cell therapy, neurodegenerative diseases

## **1. Introduction**

The eye is an excellent structure, both an optical and a neuronal device. There are many diseases related to the eye. Each anatomical part of this organ may show a defect and cause an eye defect. Diabetic retinopathy is one of the most common complications of type I and type II diabetes. One of the main causes of blindness worldwide is diabetic retinopathy. Although glucose controls are helpful for other diabetic complications, they cannot prevent the development of retinopathy. While many studies have been done on the physiology of the retina, there are many unknown dark spots. Studies suggest that radicals derived from reactive oxygen play an important role in the development of diabetic retinopathy. Due to high oxygen consumption, the brain and retina are very sensitive to oxidative stress. Oxidative stress has been found to cause brain and retinal damage in both diabetic humans and experimentally diabetic rats. Although various hypoglycemic drugs have been developed for the treatment of diabetes mellitus (DM), complications associated with diabetes remain major medical problems. Therefore, the development of new treatments is of great interest. The mechanisms in the development and progression

of diabetic retinopathy are not yet fully understood as they are multifactorial and complex. Stem cell therapies for retinal diseases have been around for a long time. Few clinical trials are currently showing improvement [1].

The eye is the site of many acute or chronic physiopathological disorders, reversible or not, that can lead to partial or total vision loss or major changes in the quality of patients' life. The search for innovative therapeutic strategies to correct these disorders is an important current issue. Gene and cell therapies are powerful therapeutic tools, but controlling the properties and spread of the injected material is a parameter that limits its application in humans. Anatomical isolation of the eye and ease of access, on the other hand, enable the use of such treatments, which have been previously developed in tissues and whose clinical application is complex [2].

Hillard Lazarus used mesenchymal stem cell (MSC) for the first time in 1995. Today, there are more than 400 applications in a wide variety of clinical fields such as inflammatory pathologies or immunological, fibrotic, or neurological disorders [3].

The use of MSC, which has a great potential, is promising for the treatment of many degenerative disorders, including the eye. In retinal degenerative diseases, MSC ameliorated retinal neurons and retinal pigmented epithelial cells in both *in vitro* and *in vivo* studies [1]. Diabetes is among the largest medical emergencies in the world. Hyperglycemia is responsible for a wide number of complications, with the vascular ones representing the leading cause of mortality. Stem cells have the unique ability to originate any organ or tissue and are capable of self-renewal. Among stem cells, great clinical interest is reserved for MSC [4].

### **2. Diabetes and diabetic retinopathy**

The development of modern life has brought with it an inactive life [5]. The human population is constantly increasing, and diseases are also increasing. In addition, the expectation of prolonging life, lifestyle, and dietary habits that support obesity creates possible conditions for the development of diabetes. Diabetes is shown as the third cause of death in industrialized countries after cardiovascular diseases and cancer. It is stated that about 110 million people on a global scale suffer from diabetes mellitus. This type of diabetes is also called diabetes mellitus. The main symptom of this disease is the presence of sugar in the urine. A diabetic patient occurs every 8 minutes according to the research of a health institution. DM is the inability of sugar to enter the cell and perform its function as a result of the insufficiency of pancreatic insulin secretion or the ineffectiveness of insulin or the inability of insulin to function due to structural defects in the insulin molecule. Insulin produced in the pancreas is responsible for the transition of blood glucose into cells. When insulin is deficient, the level of glucose in the blood increases and it increases the permeability of the vessel by causing defects in the inner surface and outer wall of the vessel in the vascular tissue. Diabetes damages the retina the most in the eye tissue. It is predicted that diabetes mellitus will rise sharply in the next decade. Patients with diabetes suffer from life-limiting and threatening complications and suffer from diseases such as stroke, peripheral arterial diseases, and retinopathy. [6]. Diabetic retinopathy is the most common microvascular complication of DM, resulting in blindness worldwide. Diabetic retinopathy (DR) is a global problem, affecting approximately 100 million people worldwide. Blindness is 25 times more common in diabetic patients than in non-diabetic patients. DR is the most common cause of blindness in patients aged 20–64 years in developed countries. The prevalence of the disease is related to the age of the cases and the duration of the disease. Biochemical changes detected in diabetic retinopathy increased

#### *Diabetic Retinopathy and Stem Cell Therapy DOI: http://dx.doi.org/10.5772/intechopen.100812*

oxidative stress, nonenzymatic glycosylation, protein kinase-C activation, polyol pathway, and increased nitric oxide [7].

Retinal neurons provide normal visual function. Vision loss in diabetes should be explained as a disorder in the function of neurons. To date, most research has generally focused on retinal vascular changes rather than the effect of diabetes on the neural retina. As a result of many studies, it has been determined that changes in neuronal function and vitality are effective in the pathological mechanism of diabetic retinopathy that starts in the early stage of diabetes. Neurophysiological changes have been observed immediately after the onset of diabetes in both humans and experimental animals [8].

The most common cause of retinopathy is diabetes. Retinopathy is responsible for about a third of vision loss and blindness in children. Microaneurysms, nonperfusion capillaries, hemorrhages and/or lipoprotein exudates, which are the onset of DR, indicate that DR is primarily a microvascular disease [9]. There is ample evidence of early retinal neurodegenerations in diabetes. Neuronal degenerations and early retinal disorders were observed in some animal models and studies in humans before the onset of diabetic vasculopathy [10]. Neurodegeneration, which causes thinning of the retina layer in animal studies, is not only limited to cell death and tissue loss but also causes functional disorders in neurotransmitters [11]. The most prominent feature of neurodegenerative diseases is increased neuronal loss with apoptosis. Increasing neuron frequency is accepted as an important component of pathology in diabetic retinopathy. Early studies characterized vascular lesions in postmortem specimens of human retinas [12–14].

Indeed, neurophysiological changes have been observed immediately after the onset of diabetes in both humans and experimental animals. It has been reported that vascular changes such as permeability changes during diabetes occur 8 days after the onset of diabetes in rats. Capillary dilation and increased blood flow are the earliest signs of diabetes in both humans and animals. Capillaries begin to close within a few years in dogs whereas in about 1 year of diabetes in rats. Typical retinopathy begins to develop in humans at 5–10 years, with microaneurysm, hemorrhage, macular edema, and neovascularization. The neural retina is transparent and invisible, so it is not visible on clinical examination. Vascular changes provide information about the course of the disease and the possibility of blindness. Apart from insulin therapy, the only proven treatment is laser photocoagulation, which destroys retinal regions with overt vascular disorders. This manipulation reduces macular edema and can improve visual acuity, but it cannot restore normal vision and prevent neuronal loss. If neurodegeneration begins shortly after the onset of diabetes, irreversible neuron damage occurs during laser therapy. Early neurophysiological and neurodegenerative changes should be considered as targets for current DR treatments. Psychophysical measurements also showed changes in vision in the early stage of diabetes onset. Contrast sensitivity decreases especially at mid and low spatial frequencies [1, 15].

Obesity is a major health problem in the world that is responsible for type II diabetes mellitus (DM) and its serious complications, such as retinopathy, cardiovascular disease, and nephropathy. In diabetic eyes, neovascularization results in blindness through a vitreous hemorrhage, retinal detachment, or glaucoma. Retinal hypoxia is the crucial factor for these complications [16]. Diabetic retinopathy is one of the most common complications of type I and type II diabetes. One of the main causes of blindness worldwide is diabetic retinopathy. Although glucose controls are helpful for other diabetic complications, they cannot prevent the development of retinopathy. The pathology of retinopathy is due to the deterioration of the vessels of the eye, which occurs due to various metabolic disorders in diabetic patients. These metabolic disturbances range from the level of vascular endothelial growth

factor (VEGF) to the accumulation of end products of its glycosylation. The primarily tissue-damaging effects of chronic hyperglycemia cause a complex interplay of multiple mechanisms, which cause abnormal permeability within the retinal vessels, and occlusion with ischemia and subsequent neovascularization. Current treatments include laser photocoagulation and vitreotomy, but these treatments are not curative and do not target the pathological mechanism of the disease. Various studies have been conducted in diabetic rats and human models. Immunohistochemical studies were able to show that intravitreally injected stem cells were localized to the inner retina and it has been stated that this increases visual function. Human clinical trials are ongoing to evaluate the safety, success, and utility of hematopoietic stem cell (HSC) injection in treating retinal vascular diseases. Two patients with diabetic retinopathy injected with HCC showed improvement in visual acuity and ophthalmic measurements even 12 weeks after treatment. The mechanism of the behavior of HSC is unclear, but is thought to be dependent on paracrine signaling. In animal models, intravitreal HSC has been shown to improve retinal damage caused by light, ischemia, and diabetes. Apart from HSC, other stem cells such as mesenchymal stem cell (MSC), endothelial progenitor cell (EPC), and adipose stromal cell are also being investigated for their use in the treatment of diabetic retinopathy. Diabetes mellitus causes both functional and structural deficiencies by affecting both the peripheral and central nervous systems. Peripheral disorders develop within a few weeks after the onset of diabetes, while central disorders take months to develop [17]. Diabetic retinopathy is a major complication of diabetes. However, the effect of a prediabetic condition on the retina has not been clarified. Prediabetes refers to a metabolic disorder defined by glycemic variables lower than diabetes but higher than normoglycemia and considered a high-risk condition for the development of diabetes. It has been stated that the majority of prediabetic patients will eventually develop diabetes [18, 19]. Current treatments for DR as laser photocoagulation, intravitreal anti-VEGF agents, intravitreal corticosteroids, and vitreoretinal surgery are applicable only at advanced stages of the DR and are associated with significant adverse effects [20]. Therefore, new treatments for the early stages of the DR are needed. Retinal diseases are the leading cause of vision loss in the world. Because of the ability of stem cells to self-renewal and differentiation to various types of cells, stem cells are becoming an attractive source of cell therapy in repairing damaged cells as retina pigment epithelium or photoreceptors. Consequently, retinal stem cell therapy is one of the promising therapeutic alternatives to recover vision [21].
