Managing Type 1 Diabetes from Gynecological Waste: Trash to Treasure

Historically, type 1 diabetes has been considered a disorder in children and adolescents, but this perception has changed over the past decade, so age at onset of symptoms is no longer a barrier. Polydipsia, polyphagia, and polyuria (early trio of symptoms associated with the onset of the disease) and apparent hyperglycemia are always diagnostic symptoms in children and adolescents, and at a lower rate in adults [1]. Type 1 Diabetes Mellitus (T1DM) is generally considered to have an autoimmune etiology, which occurs as a result of the destruction of irreversible and specialized insulin-producing cells that produce pancreatic β cells in the islets of Langerhans [1,2]. Likewise, there is an urgent need to develop new therapies that will help not only to manage the disease, but also hopefully provide a real cure for DM [3]. One potential therapy for diabetic patients is infusion of donor islets of Langerhans into the hepatic portal vein. In this procedure, islets containing the insulin secreting b cells are transplanted from a cadaveric donor to the patient. This procedure has been found to be effective in removing T1DM patients from insulin treatment to some degree. However, there is a variation in the quality of donor cells that continues to lead to a split in the success of the results [4]. β cells play a critical role in glucose homeostasis by sensing blood glucose and releasing insulin to maintain physiologic glucose levels within a relatively narrow range [2]. The blood of the umbilical cord is filled with T cells (Tregs) and many types of stem cells, which show the ability to detoxify, and hold promise in their ability to restore the tolerance associated with pancreatic islet cells through the correction of immune responses and compression T cells. Recently, the use of autologous umbilical cord blood or body cells from cord blood has been suggested as a new treatment for T1DM, with less harmful benefits to donors, less behavioral anxiety, lower incidence of Graft-Versus-Host Disease (GVHD) and more readily available [5]. Type 1 Diabetes Mellitus (T1D) is an autoimmune disease that destroys β cells. As a result, insulin secretion and the regulation of glucose levels in the blood are impaired. The onset of the disease usually occurs between 6 and 12 years of age [6]. About 382 million people worldwide are affected by diabetes; the rate is expected to increase to 592 million by 2035 [7]. World Health Organization (WHO) and American diabetes association has classified T1DM immune-mediated and idiopathic disease. In diabetic patients, glycosylated hemoglobin and blood sugar levels help to determine diabetes while low levels of serum C-peptide serve as the most acceptable indicator of T1DM diagnosis [8]. The disease is believed to be autoimmune in nature and triggered by several factors like seasons of autumn and winter, viral/bacterial infections and environmental pollutants [9]. The defective insulin release characteristic of T1DM reflects progressive β cell destruction within the range of 60-100%, counting on disease duration 4-7, also as functional defects (for example, defective glucose-induced insulin release and delayed conversion of proinsulin to insulin) that are probably caused by local release of proinflammatory mediators by infiltrating immune cells. Pancreatic pathology among patients with T1DM is different, with varying degrees of insulitis and cell loss seen in different lobes of the pancreas [10]. Patients with high b-cell mass initially experience less microvascular complications and less hypoglycemic events than those of patients with high b-cell mass. In face of this, b-cell preservation is another important goal in the management of type 1 diabetes and related complications [11]. The microbiome, thought about the “second genome” of the host, is changed over into Type 1 Diabetes Mellitus (T1DM) by patients with dysbiosis. Dysbiotic gut microbiota can reduce MSC treatment, and moderation of gut microbiota can help improve the results of MSC transplantation. Minor immune to intestinal dysbiosis of the gut has been suggested as an immunosuppressant for T1DM. In addition, dysbiosis of the gut microbiota can also affect the function of the intestinal barrier. It has been suggested that dysfunction of the intestinal tract in T1DM may increase the presence of gut microbiota in systemic proliferation and, in turn, cause islet cell dysfunction [12].

Stem cells can be prepared from embryonic or adult stem cells. However, the use of embryonic stem cells is controversial since the accumulation of such cells is achieved by killing embryos. For this reason, embryonic stem cell accession or possession is restricted in most states or excluded from public funds [13]. The autoimmune destruction of insulin producing cells that characterizes this disease requires a constant supply of insulin to maintain normal glycemic level. The shortage of transplantable human islets have evoked a large-scale interest in probing stem cells as an alternative sources of cells [14]. They can be derived from many types of tissues and organs such as bone marrow, umbilical cord, placenta, cartilage, and adipose tissue [15]. The use of Stem Cells (SCs) holds great promise for the cure of T1D due to their propitious immunological characteristics and their regenerative capabilities [16]. The immunomodulation properties of stem cells are often helpful to regulate a balance between β-cell destruction and their regeneration. Mouse and human hepatic stem cells were differentiated into insulin-secreting β-like cells and used to overcome the condition of hyperglycemia. BM-MSCs are additionally ready for graft acceptance and diminish autoimmunity [17]. There are small numbers of stem cells in the human body that after division with mitosis can differentiate into daughter cells or create newer stem cells. Maintenance and activation of their differentiation potential is fundamentally influenced by the microenvironment (cellular and humoral). Depending on the degree of differentiation, the ability to regenerate themselves, and the origin of many stem cell types can be differentiated. In terms of their plasticity totipotent, pluripotent, multipotent and weak stem cells are present. Large cells (e.g., zygote, spore, or morula) can form any human cell or even the entire body. In the case of pluripotent cells, the chances of forming a complete functional organization are limited. Many stem cells are able to create specific types of daughter cells. Under physical conditions, they ensure continuous tissue regeneration, replace dead somatic cells, and after injury participate in regeneration of the affected organ (Figure 1). Unipotent cells are precursor/progenitor cells with limited plasticity [18]. In recent years, Mesenchymal Stem Cells (MSCs) have been highlighted as a novel regenerative therapy for their multipotency, self-renewal, low immunogenicity and high immunomodulatory properties. Exosomes derived from Adipose Tissue-Derived Mesenchymal Stem Cells (AD-MSCs) have immunomodulatory effects of T-cell inflammatory response and reduction of clinical symptoms on streptozotocin-induced of the Type-1 Diabetes Mellitus (T1DM). Since transplantation of multipotent stem cells renders potential risks, secretome derivatives of these cells may be considered as promising practical therapeutics in regenerative medicine for treatment of T1DM [19]. An effective method is to save the remaining cells, restore cell function, and protect the replace IPCs from autodestruction. Pluripotent stem cells, including Embryonic Stem (ES) and induced Pluripotent Stem (iPS) cells offer a valuable alternative to supply the required cells to substitute organ transplants but also serve as a model for learning the onset and progression of the disease, resulting in better treatments [20]. Three intraperitoneal injections of ADSCs can reverse hyperglycemia in 78% of diabetic NOD mice, characterized by increased insulin, amylin, and glucagon like peptide 1 levels. Early onset diabetes recovery occurs by blocking the immune response that protects CD4+ Th1 and improving regulatory T-cells near lymph nodes. These results are the first direct evidence for ADSCs in balancing the autoimmune response, while MSCs have been widely investigated for their immunomodulatory properties in cellular transplantation [21].

Figure 1: Umbilical cord blood stem cell applications.

UCB is preferable due to its immediate availability, absence of risk to the donor (and, if autologous, to the recipient as well) low risk of graft-vs-host disease, and increased capacity for expansion The ability of UCB-derived stem cells to differentiate into a variety of non-blood cell types, including hepatocytes, neural cells, and endothelial cells has already been documented. They have superiorities including low immunogenicity, non-invasive harvest procedure, gynecological waste, easy expansion in vitro, and ethical access compared with stem cells from other sources. Therefore, HUC-MSCs can be a promising target for cell-based therapy [22]. As further evidence of the potential use of UCB in T1D therapies, UCB stem cells have successfully been directed in vitro to differentiate into insulin and c-peptide–producing cells. Because cord blood contains an outsized population of immature unprimed highly functional regulatory T lymphocytes, this might be the foremost important reason for exploring therapeutic applications of UCB in T1D. The number of highly active T cells in UCB can work to reduce the inflammatory response of cytokines and increase the ability of active T cells, which play an important role in the cellular selfregulatory process [23].
I. UCB is an abundant stem cell source, which can be easily obtained with no risk to the donors;
II. They do not require additional intervention, such as stem cell stimulation, immune ablative, bone marrow transplantation
III. Increase in cell proliferation
IV. Due to the low expression level of Major Histocompatibility Complex (MHC) antigens and costimulatory molecules, UCB-derived stem cell can easily escape from the immune recognition by the recipient lymphocytes and will not induce the proliferation of allogeneic lymphocytes after transplantation. Thus, the UCB-derived stem cells transplant does not require a perfect match of MHC as bone marrow transplants do.
V. UCB-derived stem cells are the youngest cells from a human being with a minimal DNA damage caused by environmental and endogenous factors.
VI. Human UCB cells pose a lower risk of viral contamination due to the low placental transmission rates during prenatal life [5].
The Umbilical Cord (UCB) plays a vital role in the transport of nutrients and oxygen between mother and fetus. Because it has no ethical issues and is easy to diagnose without invasive methods, human Umbilical Cord (hUCB) has become a valuable medical product [24]. Umbilical cord blood is rich in Tregs, which activates and suppresses antigen regeneration, and is also a source of haematopoietic cells and pluripotent stem. Therefore, there is a strong scientific reason behind cord blood to prevent or delay the onset of type 1 diabetes [25]. Cells derived from umbilical cord blood may represent an important biological resource for β cell generation, as well as a source of immune-modulatory cells for T1DM therapy. Human umbilical cord blood has great potential as a rich source of stem cells, including UCB-MSCs and UCB-SCs, which can be readily isolated from umbilical cord blood without ethical problems (Table 1). The properties of weak immunogenicity and strong immunoregulation make these cells promising for treating T1DM [24]. The cord blood for preservation and subsequent use is the one that is obtained from the umbilical cord after birth. Although, the HUCB was discarded in the past, recent studies have shown that it is a rich source of stem cells that are therapeutically useful in many malignant and nonmalignant diseases. Consequently, HUCB stays a choice to bone marrow transplantation in clinical practice [26]. Based on available preclinical data and the agreement that infusion of minimally manipulated autologous cord blood cells was likely to be extremely safe [23].

Table 1: Advantages and disadvantages of human umbilical cord blood.

Cells taken from the umbilical cord blood may indicate an important cell for β cell generation, as well as a source of antibodies to T1DM treatment. The characteristics of weak immunogenicity and strong immunity make these cells promising to treat T1DM. In conclusion, with promising data from preclinical studies and clinical studies, therapeutic implants of blood-derived umbilical cord cells, whether UCBMSC or UCB-SCs, can oversee the safe and effective treatment of T1DM patients.

The authors are thankful to the Principal, Dr. Sohan Chitlange, and the management of Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pune. We are also thankful to Dr. D. Y. Patil Vidyapeeth, Pune, for extending continuous support and guidance to write this paper.

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