ype 1 diabetes (T1D) is a chronic disease characterized by inadequate or absent insulin production due to the autoimmune destruction of beta (β) cells in the pancreas. It was once called "juvenile diabetes" since the disease frequently occurs in children, but it can also develop in adults. According to the International Diabetes Federation, an estimated 700 million adults will suffer from diabetes by 2045. Although the exact cause of diabetes remains unknown, it is hypothesized that genetic factors, environmental factors, and exposure to certain viruses play a role in the development of T1D. To date, exogenous insulin is the most common treatment for T1D. However, it is not a cure for the disease. Islet cell transplantation and pancreatic transplantation are two additional treatments that have gained popularity in recent years, but their clinical application may be limited by the need for high doses of immunosuppressants, the rarity of human cadaveric islets, and the need for extensive surgery in pancreatic transplantation. Mesenchymal stem cells (MSCs) are a highly promising novel treatment for T1D and their discovery has advanced biological sciences by allowing for modification of cell fate and the development of higher-order cellular structures. They play an essential role in lowering levels of fasting blood sugar, hemoglobin A1c, and C-peptide, and in treating microvascular complications associated with T1D. However, some of the disadvantages of its use in clinical practice are limited to its method of collection, proliferation rate, cell activity with age, and the risk of tumour formation identified in some studies. Large-scale studies are required to discover the mechanism of action of MSCs after administration as well as the optimal route, dose, and timing to maximize the benefits to patients. This article focuses primarily on the role of MSCs in the treatment of T1D and compares the feasibility, benefits, and drawbacks of MSCs in the treatment of T1D. Introduction & Background Type 1 diabetes (T1D) is a chronic immune-mediated disease characterized by the destruction of pancreatic β-cells, resulting in absolute insulin deficiency and hyperglycemia. It is primarily a disease of youth, accounting for approximately 85% of cases in people under the age of 20 and 5% to 10% of all diagnosed cases of diabetes [1,2]. Although the exact mechanisms are unknown, T1D is thought to develop through immune system activation against β-cell antigens and the initiation of proinflammatory cytokine responses. Environmental factors, obesity, viral infections, and nutritional factors were found to play a role in the pathophysiology as well [3]. T1D predisposes to a number of comorbidities, such as obesity, chronic kidney disease, metabolic syndrome, coronary artery disease, and hypertension. Such predispositions may account for higher mortality rates, affecting up to one in 10 adult patients within a year of diagnosis [4]. In fact, diabetic nephropathy (DN) is said to account for up to 40% of end-stage renal disease (ESRD) cases worldwide. Cardiovascular events account for up to 70% of T1D deaths and are 10 times more common in diabetics than in non-diabetics [5]. Therefore, it is critical to focus on novel therapies that aim to reduce the risks of acute complications such as hypoglycemia and diabetic ketoacidosis (DKA) while avoiding long-term complications such as DN, neuropathy, and retinopathy [5]. Exogenous insulin is currently the most prevalent treatment for T1D. Although exogenous insulin administration may be life-saving, it is not a cure for the disease. If patients are unable to maintain tight glycemic control by strictly adhering to their insulin regimen, they will invariably develop severe secondary complications that may shorten their life span [6]. Exogenous insulin is not a viable substitute for normal pancreatic islet function, mainly due to the absence of accurate temporal glucose control over time [7]. The administration of insulin can also result in hypoglycemic episodes [6]. A cross-sectional study conducted in Mexico revealed that patients' fear of hypoglycemic episodes prevented them from complying with their insulin treatment plan [8]. Replacement of the defective insulin-producing cells (IPC) is yet another potential therapy for T1D. This is possible through transplantation of the pancreas. Since the first pancreatic transplant took place in 1966, over 50,000 such transplants have been performed worldwide. Patients with T1D who receive a pancreatic transplant were found to have a reduced risk of subsequent complications and a longer life expectancy [9]. However, since transplantation is a major surgical procedure, patients must be fit for surgery [6]. Transplants necessitate permanent immunosuppression, which may put patients at risk for a variety of infections. In addition, they are associated with a number of postoperative complications, such as pancreatitis, due to low tolerance to cold ischemia, bleeding, thrombosis, and anastomotic leakage, which may require relaparotomy and graft pancreatectomy in recipients [9]. An alternative to pancreatic transplantation that is both safe and effective is islet cell transplantation. Scharp et al. published the first case of allogeneic intraportal islet transplantation for T1D in 1990, which led to short-term insulin independence and paved the way for clinical islet transplantation [10]. Despite the fact that the immunosuppressive regimen reported from Edmonton, Canada, also known as the Edmonton protocol (the Edmonton protocol introduced significant adjustments to the transplantation procedure, including the use of an immunosuppressive regimen free of steroids and the transplanting of an average islet mass of 11,000 islet equivalents per kilogram) has achieved unprecedented success in islet transplantation in terms of insulin independence, a number of factors continue to influence the outcome of this minimally invasive procedure [11]. Islet cell transplantation can induce a rapid inflammatory reaction in the circulation, leading to the loss of the vast majority of transplanted islets. The use of large doses of immunosuppressants during transplantation compromises the long-term viability and function of the graft, and the need for long-term immunosuppressive medications after the transplant poses a risk of organ damage, malignancies, new infections, and new-onset T1D in patients [12]. The high cost of islet transplantation and the paucity of human cadaveric islets highlight the urgent need for innovative pancreatic islet transplantation procedures [7]. This is where stem cells (SCs) pose an important role. SCs are a highly promising novel treatment for T1D due to their ability to differentiate into several cell types and their regenerative potential. SCs can be categorized into four basic groups based on their origin as shown in Figure 1. Mesenchymal stem cells (MSCs), also called mesenchymal stromal cells, are non-hematopoietic, multipotent SCs. They can be extracted from a variety of sources, including bone marrow, liver, kidney, adipose tissue, urine, umbilical cord blood, umbilical tissue, Wharton's jelly, placenta, and even endometrial tissue (menstrual blood-derived endometrial stem cells - MenSC). Several surface markers, including CD73, CD90, and CD105, can be utilized to identify MSCs. Due to their ability to differentiate into numerous cell types, they can be used to repopulate damaged tissues [13,14]. MSCs have gained enormous popularity in the treatment of T1D because of their ability to regulate fibrosis and tissue regeneration, as well as their ability to modulate immunological function. In addition, they produce a variety of secretory molecules, such as cytokines and exosomes, which play an essential role in the treatment of T1D [15]. Studies on animals treated with MSCs have shown a significant reduction in hyperglycemia, as evaluated by a decrease in serum glucose and an increase in insulin and C-peptide levels. In addition, they were able to restore normal levels of lipid fractions. Using MSCs lowered the serum levels of both liver and kidney function markers in diabetic rats, demonstrating their hepato-renal protective benefits in T1D [16]. Several mechanisms have been discovered to play a role in the management of T1D by MSCs (Figure 2).

The Role of Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes

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Monday 3 October 2022

The Role of Mesenchymal Stem Cells in the Treatment of Type 1 Diabetes