**3. Stem cells**

The organism begins to form from a cell and then develops into a complete organism with more than 200 cell types. This phylogenetic trend, the tendency to switch from pluripotent cells to mature cells is an integral part of human development. This process, in which cells differentiate and turn into cells without plasticity, is necessary to form all special tissues of the human and to minimize the risk of tumor proliferation. Basically, for a cell to be accepted as a stem cell, this cell should first be able to renew itself without losing its plasticity, and then lose its plasticity and differentiate into different sub-cell types [22]. A stem cell is an undifferentiated cell with the capacity to self-renewal and differentiate. These cells have also the capacity to differentiate into special cells that make up tissues and organs. Self-renewal is the capacity for a cell to reproduce indefinitely by maintaining its undifferentiated state. Differentiation potential is the capacity for a cell to differentiate into one or more types of mature cells.

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

In addition, stem cells are also characterized by maintaining a certain calmstagnant state, apart from their capacity for self-renewal and differentiation. This quiescent phase is the G0 phase of the cell cycle, in which cells enter in the absence of mitotic factors. With this calm phase, stem cells can protect themselves against possible "attacks" and maintain their vitality. However, none of these features are sufficient to define the 'root' character of the cell. In fact, it should have the potential to rebuild the tissue's excellent function in the long run. This means a large number of cellular divisions and differentiation *in vivo*. These properties also play a vital role in organogenesis and adult tissue regeneration. There are many stem cells used and studied in research. Particularly, some researchers can find new stem cell sources today [23–25].

The two largest types of stem cells in mammals are embryonic stem cells isolated from the inner cell mass of the blastocyst and adult stem cells found in most adult tissues.

#### **3.1 Embryonic stem cells (ESC)**

They are the first discovered and studied stem cells. They are cells that can renew themselves and have the capacity to differentiate into all cell types that can form a whole organism.

#### **3.2 Adult stem cells**

With the development of the embryo, embryonic pluripotent stem cells are replaced by stem cells with a more limited capacity, which will provide organ and tissue formation. Cells of different tissues are now specialized. Organs need a mechanism to regenerate cells by replacing cells lost by apoptosis or lesion, thus maintaining their homeostasis. An adult loses about 20 billion cells in a day. This requires a permanent restructuring system [26]. Some organs such as the brain, heart, and kidney are less regenerated [27]. On the other hand, tissues such as bone marrow, skin, and intestines are constantly renewed. To ensure the regeneration prosess, organs have a cell reservoir; adult stem cells which serve throughout life. Their stocks are provided by the balance between self-renewal and differentiation capacities. Adult stem cells are also known as somatic stem cells. It is assumed that all organs of the body have mature stem cells, and in most organs, they are active throughout life. They constantly form new cells to ensure tissue regeneration (skin, cornea, bone marrow, intestine) [28–30]. In some organs, these cells become active after birth and then go into dormancy. We see them in organs with slow or almost no cellular regeneration; it is seen only in organs such as the brain and liver, where stem cells divide only during serious injuries or rarely [31, 32]. Hematopoietic stem cells, stromal stem cells, and stem cells in organs are adult stem cells.

Bone marrow contains two types of cells: hematopoietic stem cells (HSC) and stromal mesenchymal stem cells (MSC). HSC can form all mature hematopoietic cells such as myeloid and lymphoid. MSC plays a supportive role in hematopoiesis. Bone marrow also contains other types of cells. Progenitor endothelial cells (PEC) are found in the marrow as well as adult multipotent progenitor cells [33]. When necessary, PEH enters the circulation and plays a role in angiogenesis. In addition, some studies refer to bone marrow stem cells (F-MSCs), which represent a heterogeneous stem cell population. These cells can differentiate into many different types of cells, such as hepatocytes, endothelial cells, epithelial cells, cardiac or skeletal muscle cells, neuronal cells, or astrocytes. This indicates that bone marrow cells have the potential to differentiate into cells of another tissue [34]. Stem cells are ubiquitous. Some niches are yet to be discovered. Although bone marrow-derived

stem cells have been cited as a potential resource for regenerative therapy, their potential and usefulness are still open to debate [35, 36].

Deterioration in tissues or organ functions for any reason constitutes a very important problem in terms of seriously affecting an individual's quality of life. For this reason, regenerative medicine is concerned with repairing the damage and restoring normal body functions through stem cell therapies. Advances in stem cell research have shown cell-based therapy as a useful option to treat medically incurable diseases [36]. Stem cells can migrate to damaged tissue. The effect and cellular mechanisms of stem cells vary according to their environment. They have excellent plasticity that allows these cells to adapt to their environment and act appropriately [33].

"Plasticity" is the ability of a stem cell to acquire different differentiation programs under certain microenvironmental conditions. Endogenous MSC or exogenously administered MSC can migrate to the injured tissue and participate in its healing. The therapeutic effects of MSC can be attributed to its ability to secrete a wide variety of paracrine factors. These mechanisms are likely independent, but they can also act together. In many cases, a combination of these protective mechanisms can work together to heal the damage [37]. However, the mechanism of the therapeutic effect of stem cell is still open to debate. There are two basic explanations; these are cell differentiation and the paracrine effect of stem cells. The combination of these two mechanisms seems to be a third theory [38].

#### **4. Mesenchymal stem cells and retinal degenerations**

Retinal degenerations are pathologies that affect the light-sensitive cells of the retina, photoreceptors, cones, and rods. Cell therapy is accepted as an interesting alternative for retinal degenerations. A mouse model of retinal degeneration has been shown to improve visual function after transplantation of photoreceptors [39]. Other cells, including MSC, also show great potential by altering photoreceptors or protecting against degenerations due to their paracrine effects [40]. Some researchers also emphasize that MSC can differentiate into retinal cells, especially photoreceptor-like cells. This plasticity feature of MSC has been observed *in vitro* [41]. It has also been observed *in vivo* by subretinal injection in a rat model with retinal degeneration [42]. These results reveal the possibility of regenerative therapy in pathologies involving photoreceptor losses.

In general, cellular therapy works in two ways: to replace dead cells in the tissue to restore tissue function or to prevent/attenuate/slow tissue degeneration by reducing inflammatory infiltration or reduce apoptosis and cell death phenomena.

### **5. Stem cell and eye**

The eye is a small organ, and the number of stem cells required therapeutically is theoretically less than in larger organs. Compared to other internal organs, the retinal environment is easily accessible with small-gauge vitrectomy needles, greatly increasing the potential for stem cell-based therapy for the treatment of retinal degenerative diseases. The retina is layered and thin. It depends on the preservation of cells, nerve anatomy, and synaptic networks to maintain vision. Retinal neuron connectivity is an important therapeutic goal to alleviate blindness in millions of people worldwide for the preservation or restoration of the original neural structure of the retina and photoreceptor [43]. The emergence of studies shows the possibility of cell regeneration in the adult central nervous system, which makes it possible

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

to envision the implantation of stem cells or progenitor cells as an approach to cell therapy. The restorative approach offers strong hope, given that key questions about the biology of development need to be explored. The transplantation of differentiated or undifferentiated retinal tissue (embryonic, newborn) in the subretinal position of the graft poses the problem of its structural and functional organization.

It is seen that different types of stem cells are used considering transplantation studies. When we look at transplantation studies, in studies using different types of stem cells (retina progenitor cell, neural stem cell, bone marrow-derived stem cell, and embryonic stem cell), although they settle in the retina, they are not able to express retinal-specific markers and cannot establish synaptic connections are encountered [44].

The discovery of stem cells has caused great excitement in the hopes of using such treatments to restore vision. Already, stem cells in the anterior segment of the eye have a remarkable clinical effect. Stem cell therapy provides re-epithelialization of the cornea and improves vision. The trabecular meshwork, located on the inner side of the junction of the sclera and the cornea, can also be regenerated with stem cells [38]. However, the most interesting studies have been done in the posterior segment of the eye. Most retinal degenerations begin with the loss of a neuron or damage to a neuron. Therefore, these cells should be replaced with a cell layer that is differentiated and functional in the appropriate medium. Sometimes pathology develops and destroys many cells. In this case, a graft consisting of several layers is required. To perform a transplant treatment for blindness, progenitor neuronal cells are isolated and transferred to different cells of the retina.

Studies on neuronal cell cultures that can differentiate are done. Today, very few of these differentiation mechanisms have been fully elucidated. Therefore, the use of cell transplantation in the retina seems distant [45].

Considering that stem cell therapy is promising in retinal diseases, studies were started with embryonic stem cells, and induced pluripotent stem cells were obtained. Many retinal cells such as retinal pigment epithelium, photoreceptors, and ganglion cells were obtained from induced pluripotent stem cells [46].

It is stated that the neuroretina, which is attached to the pigment epithelium (RPE), has a complex structure. Therefore, it has been stated that there are three different cells that can be considered in cell therapy: neuroretina (photoreceptors, bipolar cells, ganglion cells, and glial cells), RPEs, and vascular endothelial cells. Depending on retinal diseases, strategies to place different cells need to be developed [47].

## **6. Conclusion**

Diabetic retinopathy (DR) is one of the largest causes of vision loss worldwide. The use of autologous stem cells for organ reconstruction offers a potential solution for the replacement of tissue or whole organs mechanisms in the development and progression of DR are not fully understood yet. Although many studies have been done about retinal physiology, many unknown dark spots are available about it. Stem cell therapy appears to be a possible option both to prevent neurovascular damage and to repair the damaged retina. Mesenchymal stem cell attracts great attention in retinal degenerations due to their ability to differentiate into neurons. However, the way and amount of stem cell administration will create different effects, it is important to know the effect of cell therapy on body after administration in relation to its use in the clinical practice.

To date, no treatment has been developed for the regeneration of retinal vasculature damage resulting from prolonged hyperglycemia. Cell therapy seems to be a possible option both to prevent neurovascular damage and to repair damaged retina [48]. Although clinical evaluations and retinal autopsies of diabetic patients provide information about the progression and features of diabetic retinopathy, its pathophysiological mechanism is not yet understood. Studies on animal models continue in order to better understand the development of diabetic retinopathy at the molecular and cellular level [49]. Retina, in the nervous system, provides a suitable environment to study the functions and distribution of stem cells. It is stated that intravenously administered mesenchymal stem cell transplantation can inhibit retinal apoptotic cells, reduce inflammatory responses, and limit the spread of damage [50].

In a study in which intravitreal mesenchymal stem cell application was performed, some physiological parameters were examined and it was seen that although there were decreases in body weight in diabetics, there was no change in body weight in the group administered intravitreal stem cells. These findings were interesting for us. While it was reported that body weight increased significantly in the mouse model in which the human adipose tissue-derived mesenchymal stem cell was transplanted *via* the tail. It has been stated that intravitreal stem cell application also reduces intraocular pressure and provides a better cognitive function in the diabetic model [51].

As a result, more clinical trials should evaluate the application methods, the timing of the practice, using cell count and repetition dose of stem cell and their results. In the near future, the regenerative stem cell therapy may be a standard treatment in many degenerative eye disorders.
