Juvenile Diabetes Or Type 1 Diabetes: Stem Cell Therapy

Abstract

Type 1 diabetes is a chronic condition that affects many people. It involves little to no production of insulin in the pancreas, which leads to no glucose being absorbed into cells. This can cause many complications, so the management of Type 1 diabetes is vital. Current treatments for Type 1 diabetes involve insulin injections, monitoring blood glucose levels, and lifestyle changes, but no cure has been found. Pancreas and islet cell transplantations have also been used as treatments for Type 1 diabetes, but these are not always feasible options due to the lack of availability. Stem cell therapy has shown promising possibilities in the treatment of Type 1 diabetes, as stem cells have been shown to treat a number of autoimmune diseases. 

Introduction

About 1.25 million Americans alone are affected by Type 1 diabetes. It is estimated that 40,000 people are diagnosed with Type 1 diabetes each year, and it is expected that 5 million people will be diagnosed by 2050. Previously known as juvenile diabetes, Type 1 diabetes is “a chronic condition in which the pancreas produces little or no insulin”. Insulin is a hormone that allows glucose to enter cells in order to eventually produce energy. Type 1 diabetes usually presents itself during childhood, but it can also develop in adults. Symptoms of Type 1 diabetes can include frequent thirst, increase in urination, extreme hunger, fatigue and weakness, blurred vision, etc. The cause of Type 1 diabetes is unknown, but it is thought that the body’s immune system mistakenly destroys insulin-producing pancreatic islet cells. While there is no cure yet for Type 1 diabetes, stem cell therapy has shown promising treatment options.

In patients with Type 1 diabetes or diabetes mellitus, there is no insulin to allow glucose into cells. This causes sugar buildup in the bloodstream, which can lead to life-threatening complications. There are several risk factors for Type 1 diabetes, including family history, genetics, geography, and age. People with a parent or sibling who have Type 1 diabetes are at a slightly increased risk of developing the disease. The presence of certain genes can also indicate an increased risk of developing Type 1 diabetes. Interestingly enough, the incidence of Type 1 diabetes seems to increase as people travel away from the equator. While diabetes can appear at any age, there are two notable peaks for risk of developing the condition: children between 4 and 7 years old, as well as children between 10 and 14 years old. Type 1 diabetes can affect major organs in the body, which can lead to life-threatening complications. These include heart and blood vessel disease, neuropathy, nephropathy, diabetic retinopathy or blindness, foot damage, gum disease or dry mouth, and even pregnancy complications due to elevated blood sugar levels in the mother and baby. Currently, there is no way to prevent Type 1 diabetes.

The loss of beta cells, or insulin-producing cells, is characteristic of Type 1 diabetes. This results in little to no production of insulin in the pancreas. Without sufficient insulin, glucose builds up in the bloodstream. Alpha cells regulate the secretion of glucagon. These cells are often preserved in Type 1 diabetes. Studies have shown that blocking glucagon uptake can improve glycemic control, thus preventing diabetes. The severity of Type 1 diabetes is directly proportional to the number of beta cells remaining in the body, as this has been shown in streptozotocin-induced diabetes. In healthy individuals, a rise in blood glucose levels, such as after a meal, signals an increase in insulin and an inhibition of glucagon secretion by alpha cells. This loss of glucagon suppression through insulin that is seen in Type 1 diabetes results in high levels of glucagon in the blood. When glucose levels fall in healthy individuals, the secretion of glucagon is triggered. In patients with Type 1 diabetes, this response is absent. The lower the number of functional beta cells, the lower the glucagon uptake, thus increasing the risk for hypoglycemia.

Type 1 diabetes can be clinically diagnosed through several different methods. The glycated hemoglobin (A1C) test shows the average blood sugar level for the past several months. This test measures the percentage of blood sugar that is attached to the protein in red blood cells that carries oxygen, known as hemoglobin. An A1C level of 6.5% of higher indicates diabetes. A random blood sugar sample can also be taken to diagnose diabetes. Here, blood sugar levels higher than 200 mg/dL suggest diabetes. The last test used to diagnose diabetes is the fasting blood sugar test. A blood sample will be taken from the patient after fasting overnight. If this blood sugar level ranges from 100 to 125 mg/dL, the patient is considered prediabetic. Anything over 126 mg/dL on two separate tests indicates diabetes.

When patients receive a diabetic diagnosis, separate blood tests are given to check for autoantibodies, which are indicative of Type 1 diabetes rather than Type 2 diabetes. Ketones in a patient’s urine also suggest Type 1 diabetes as opposed to Type 2. Repeated A1C testing after a diabetes diagnosis indicates how well the diabetic treatment plan is working for the patient. Doctors will also periodically check the patient’s cholesterol, thyroid function, liver function, and kidney function to ensure proper treatment. These treatment plans for Type 1 diabetes include taking insulin, counting carbohydrates, fats, and protein intake, blood sugar monitoring, healthy dieting, and exercising regularly. While these lifestyle changes are used to ensure lower blood sugar levels, patients with Type 1 diabetes need lifelong insulin therapy. There are four main types of insulin used. Short-acting (regular) insulin includes Humulin R and Novolin R. Rapid-acting insulin includes insulin glulisine (Apidra), insulin lispro (Humalog), and insulin aspart (Novolog). Long-acting insulin treatments are insulin glargine (Lantus, Toujeo Solostar), insulin detemir (Levemir), and insulin degludec (Tresiba). Lastly, intermediate-acting insulin includes NPH (Novolin H, Humulin N). Because insulin cannot be taken orally due to stomach enzymes that will break it down, insulin needs to be given to patients through injections or an insulin pump. Insulin injections use a needle and syringe or an insulin pen to inject insulin under the patient’s skin. For this treatment plan, a mixture of insulin types is needed to use throughout the day and night. Multiple daily injections including long-acting insulin combined with rapid-acting insulin are recommended because they better mimic the body’s natural use of insulin as opposed to insulin injections that only require one or two shots per day. With that in mind, treatment of three or more insulin injections per day has been shown to better improve blood sugar levels. The other treatment option is an insulin pump. This is a device worn outside the body with a tube connecting a reservoir of insulin to a catheter under the patient’s abdomen. The pump can be worn on the patient’s waistband, in his or her pocket, or on a belt designed specifically for pumps. Wireless pumps are another option. These pumps contain a pod that stores the insulin reservoir on the patient with a catheter inserted under his or her skin. Insulin pods can be worn on the abdomen, lower back, leg, or arm. All of these different types or pumps are programmed to dispense specified amounts of rapid-acting insulin. The steady dose of insulin is called a basal rate. This dose replaces the long-acting insulin treatment option. When patients utilizing insulin pumps eat, they need to program the amount of carbohydrates along with the current blood sugar level into the pump. This gives the patient a bolus dose of insulin that is needed to cover the desired meal and correct blood sugar if need be. While some research indicates that insulin pumps are better at controlling blood glucose levels than insulin injections, an insulin pump in combination with a continuous glucose monitoring device suggests the most effective blood sugar control. A newer treatment option for patients with Type 1 diabetes was approved by the FDA in September of 2016. This is known as an artificial pancreas for patients over 14 years of age. The implanted pancreas device works by linking a continuous glucose monitor to check blood sugar levels every five minutes to an insulin pump. This utilizes a closed-loop system of insulin delivery to automatically deliver the correct amount of insulin. Several additional medications, such as high blood pressure medications, aspirin, and cholesterol-lowering drugs might also be needed for patients with Type 1 diabetes. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are used to keep patients’ kidneys healthy and prevent high blood pressure, namely in patients with blood pressure above 140/90 mm Hg. Aspirin can be used daily to protect Type 1 diabetic patients’ hearts. Since people with diabetes are more at risk for heart disease, the American Diabetes Association recommends low-density lipoprotein (LDL) cholesterol be below 100 mg/dL, while high-density lipoprotein (HDL) cholesterol be below 50 mg/dL in women and 40 mg/dL for men. Triglycerides are another type of blood fat, and these are recommended to be below 150 mg/dL for diabetic patients. The only way to ensure that the blood sugar levels of diabetic patients remain in a proper target range is to carefully monitor it, as the American Diabetes Association recommends doing before meals and snacks, before bed, and before exercising or driving. Even more so, continuous glucose monitoring (CGM) is the newest development in monitoring blood sugar levels. The devices have also been shown to prevent hypoglycemia and lower the A1C. These continuous glucose monitors work by attaching to the body through a fine needle, located just under the skin that checks blood glucose level every couple minutes. However, CGM is not yet considered as accurate as blood sugar monitoring, so patients are encouraged to frequently check their blood sugar levels manually. One of the most important things for patients with diabetes to do is focus their diets on nutritious, high-fiber, and low-fat foods, namely whole grains, fruits, and vegetables. Aiming for at least 150 minutes of aerobic exercise per week is also recommended for patients with Type 1 diabetes to maintain a healthy lifestyle.

Along with these treatment and management methods, there are certain life circumstances that particularly affect people with Type 1 diabetes. Since hypoglycemia can occur at any time, it is recommended for diabetic patients to check their blood sugar before driving. With a blood sugar level lower than 70 mg/dL, type 1 diabetics should have a snack with at least 15 grams of carbohydrates and then retest their blood sugar to see if it is within a normal range. In terms of people with Type 1 diabetes in the work environment, they need to ensure that they will receive proper accommodations, such as additional meal breaks along with blood sugar testing. Federal and state laws are in place in order to require that employers properly accommodate workers with diabetes. Pregnancy also puts women with Type 1 diabetes at a greater risk. It is recommended that women be evaluated before trying to become pregnant in order to maintain A1C ratings of less than 6.5% prior to conception. There is a great risk for birth defects in women with Type 1 diabetes, especially when diabetes is not controlled during the first six to eight weeks of pregnancy. Old age is also an increased risk for people with Type 1 diabetes. If older patients are frail, sick, or have cognitive deficits, there is evidence that tight control of blood sugar may not be practical and could actually increase the risk for hypoglycemia. There are hopes for new potential treatments for Type 1 diabetes, such as a pancreas transplant and islet cell transplantation. With a pancreas transplant, patients with Type 1 diabetes would no longer need insulin. However, there are serious risks with these transplants, so these procedures are done only for patients with difficult-to-manage diabetes or who also need a kidney transplant. With islet cell transplantation, researchers are able to provide new insulin-producing cells from a donor pancreas. There have been issues with this procedure in the past, but better drugs and newer techniques can help prevent islet cell rejection and hopefully improve future chances of islet cell transplantation being a viable treatment option.

Stem cells are unspecialized cells within the body that have the ability to differentiate into any cell of an organism as well as self-renewal. These cells can exist in both embryos and adult cells. There are several types of stem cells based on their capacity to differentiate; these cell types include totipotent, pluripotent, multipotent, oligopotent, and unipotent. Totipotent stem cells are able to differentiate into all different cell types, even extra-embryonic tissues as well as bodily tissues and the germline. Pluripotent stem cells possess the ability to differentiate into all three germ layers, including embryonic stem cells and induced pluripotent stem cells. However, pluripotent stem cells cannot generate specific extra-embryonic lineages. Multipotent stem cells have the ability to differentiate into confined cell generations. This includes bone marrow-derived mesenchymal stem cells, dental pulp stem cells, and hematopoietic stem cells. Oligopotent stem cells show restricted lineages with the ability to differentiate a specific tissue, such as stem cells that reside on the mammalian ocular surface. Lastly, unipotent stem cells have the ability to differentiate into unilinear, such as progenitor cells involved in postnatal development. Stem cells can exist as either adult or embryonic stem cells. Adult stem cells are plastic-like adherent cells that can differentiate into bone, cartilage, and fat in vivo and are found in bone marrow, peripheral blood, and adipose tissues of adults.

Mesenchymal stem or stromal, cells (MSCs) are plastic, adherent, spindle-shaped cells that can be gathered from bone marrow, adipose tissue, and the umbilical cord, along with other tissue sources capable of differentiating in vivo. Mesenchymal stem cells have been vastly studied in recent decades since they were first isolated from bone marrow. According to the International Society for Cellular Therapy, there are several minimum characteristics that are set in order for cells to be classified as mesenchymal stem cells. These criteria are surface expression of CD73, D90, CD105 in the absence of CD14, CD34, CD45, and human leucocyte antigen-DR, plastic adherence, and most importantly the ability to differentiate into various cells such as adipocyte, chondrocyte, or osteoblast cells in vitro. While mesenchymal stem cells are mostly sourced from bone marrow, adipose tissue, and the umbilical cord, there have been several other tissues in which these cells are found. Dental pulps, endometrium, peripheral blood, the placenta, skin, synovial fluid, and muscle are several examples of new sources where mesenchymal stem cells have been found. However, the characteristics and differential ability of these mesenchymal cells can vary based on their origins in the body.

On the other hand, hematopoietic stem cells possess the ability to generate all functional hematopoietic lineages. This includes erythrocytes, leukocytes, and platelets. Therefore, the lifelong production of all blood cells is dependent on hematopoietic stem cells. Through early on research, mouse hematopoietic stem cells (HSCs) were studied through clonal in vivo assays, where labeled cells were studied for the ability of hematopoiesis after an injection into conditioned hosts. The first evidence of stem cells that form blood came from case studies in 1945 of people who were exposed to lethal doses of radiation. Scientists then duplicated this radiation sickness in mice, and they found that the mice could recover through bone marrow transplants from a healthy donor. Hematopoietic stem cells have been studied for over 50 years, and as a result, these cells are currently routinely used to treat cancer patients and patients with other blood or immune system disorders. Further along in the early 1960s, two scientists named Till and McCulloch started to analyze the bone marrow in order to determine what components were able to regenerate blood. This ultimately led to the discovery that hematopoietic stem cells can renew themselves as well as generate cells that give rise to all types of blood cells. Since the 1960s, HSC research began with studies in mice. However, this proves to be a challenge because 1 in every 10,000-15,000 bone marrow cells is thought to be a stem cell. Even further, only 1 in 100,000 blood cells is thought to be a stem cell. Tests have since then been focused on proving the self-renewal and plasticity characteristics of hematopoietic stem cells. This is still carried out based on the same proof used in mice decades ago. This consists of the cells being injected into a mouse that received a dose of irradiation that is high enough to kill its blood-producing cells; then, if the mouse recovers along with all types of blood cells, this means that the cells that were transplanted are considered stem cells. Based on these tests, scientists have determined two types of HSCs: short-term and long-term. Bone marrow cells from the transplanted mice that can be transplanted to another mouse with lethal radiation as well as regenerative the mouse’s hematopoietic system over several months are considered long-term stem cells. These cells are capable of self-renewal. On the other hand, there are cells derived from bone marrow that can immediately regenerate all types of blood cells but cannot regenerate themselves long-term under normal conditions. These cells are known as short-term stem cells that serve as progenitor or precursor cells. Precursor or progenitor cells are precursors to a fully differentiated cell that is of the same type of tissue. These cells are able to proliferate, with a limited ability to differentiate into more than one cell type. True stem cells are capable of self-renewal for an organism’s entire life, so long-term hematopoietic stem cells are currently the most important for stem cell-based therapies.

One important factor to understand when studying stem cells is the effect that age has on them. As with most things in the human body, wear and tear takes place over the aging process and causes parts of our body to not function as well as they once did. When stem cells age, their ability to differentiate into specific cell types is changed and their renewal abilities greatly lessen. Cell death, or apoptosis, senescence, and loss of regenerative potential can all result from aging in stem cells. The stem cell theory of aging “assumes that inability of various types of pluripotent stem cells to continue to replenish the tissues of an organism with sufficient numbers of appropriate functional differentiated cell types capable of maintaining that tissue’s (or organ’s) original function is in large part responsible for the aging process”. There are several molecular mechanisms that are involved in the aging of stem cells. These include telomere shortening, epigenetic dysregulation, oxidative stress, miRNA changes, as well as alterations of DNA, RNA, proteome, and other various organelles.

Due to the aging issues related to adult stem cells, embryonic stem cells have been studied as another viable option for stem cell therapy. As stated in their name, embryonic stem cells are taken from embryos during their developmental stage that occurs before implantation in the uterus. These cells, known as blastomeres, are undifferentiated and therefore has the ability to give rise to any cell in the body. After five days of development, the first differentiation event occurs when an outer layer of cells that will differentiate into the placenta separates from the inner cell mass. These inner cell mass cells have the ability to become any type of cell. However, if implantation occurs, they are differentiated into specific cell types and lose their developmental potential. If this inner cell mass is removed from its natural embryonic environment and then cultured appropriately, these cells can proliferate and renew indefinitely while maintaining the ability to differentiate into any cell type in the body. Therefore, these cells become pluripotent, inner cell mass-derived, embryonic stem cells.

Although embryonic stem cells hold promising hopes in the development of stem cell therapies, there are numerous ethical issues that come along with their use. The first human embryonic stem cell line was obtained in 1998. In order to harvest these cells, the five-day-old preimplantation embryo needs to be destroyed. Because of this, critics of embryonic stem cell research argue that since the embryo has the capability to develop into a human, there are major ethical issues that go into this research. The National Academy of Sciences created a committee in 2003 to generate guidelines for research conducted with human embryonic stem cells. Most opposition related to the use of embryonic stem cells is associated with the “pro-life” and anti-abortion movements. President Bush in 2001 allowed funding from the National Institutes of Health for stem cell research using embryonic stem cell lines that were already in existence. This policy, however, prohibited the use of further embryonic stem cell lines. In 2009, President Obama overturned President Bush’s executive order. This executive order, titled Removing Barriers to Responsible Scientific Research Involving Human Stem Cells supports responsible, scientifically worthy human stem cell research, including the use of human embryonic stem cells. A different source of embryonic stem cells involves the use of frozen embryos from women who had undergone infertility treatment and chose to donate their remaining embryos. Informed consent and confidentiality of the donor are two ethical concerns that need to be maintained when using embryonic stem cells obtained from infertility treatments.

Current research has allowed scientists to molecularly manipulate adult stem cells back into their pluripotent state to generate “induced pluripotent stem cells”. These stem cells share many of the same characteristics as embryonic stem cells, including proliferation, morphology, and gene expression, without ethical dilemmas. Multipotent stem cells have also proven to be useful in clinical settings because they have the ability to become all of the various progenitor cells for a specific germ layer or can be limited to differentiating into one or two cell types for specialized use. The best-known and studied source for these multipotent stem cells is in bone marrow, as these have been used in therapies since the 1960s in treating leukemia, myeloma, and lymphoma.

There are two main types of stem cell transplants, based on the source of the donated stem cells. In autologous transplants, the stem cells come from the same person who is also receiving the transplant. These stem cells are either removed from the patient’s bone marrow or blood. One major benefit of autologous transplants is that there is no risk of donor cell rejection because the patient is receiving his or her own cells back. On the other hand, the engrafted cells can still fail by not returning into the bone marrow to make more blood cells. Even more so, harmful cancer cells might be obtained during the collection of stem cells and then put back into the host’s body. Autologous transplants are typically used in several types of cancers, including leukemias, lymphomas, neuroblastoma, testicular cancer, and multiple myeloma. These stem cell transplants can also be used to treat multiple sclerosis, system sclerosis, and systemic lupus erythematosus. Allogeneic transplants are the other type of stem cell therapy used to treat diseases in which the stem cells come from either a matched related or unrelated donor. Here, the best option for donors is a close family member. If this is not possible, donors can be found through the national registry to find a matched unrelated donor, although these transplants are much riskier. One advantage of allogeneic stem cell transplants is the fact that donor stem cells create their own immune cells, which in turn could help kill cancer cells that remain. This is known as the graft-versus-cancer effect. Also, stem cells from healthy donors are guaranteed to be free of cancer cells. One risk of allogeneic stem cell transplants is the possibility that the graft might fail, where the transplanted donor stem cells could be killed or destroyed by the patient’s body before being able to settle into the bone marrow. Graft-versus-host-disease is also a risk of allogeneic transplants. Here, the immune cells from the donor could possibly attack healthy cells in the patient’s body, not just the harmful cancer cells. These stem cell transplants are mostly used to treat leukemias, lymphomas, myelodysplastic syndrome, multiple myeloma, as well as other bone marrow disorders.

Discussion

Hematopoietic stem cell transplants involve the administration of high-dosage chemotherapy. E. Donnall Thomas performed the first successful allogeneic stem cell transplantation in 1957. Since then, stem cell transplants have been used in treating many diseases, such as congenital disorders, autoimmune diseases, and metabolic disorders. Many different new practices have extended the availability for stem cell transplants, including matched unrelated donors, partially matched related donors, and umbilical cord blood units. In 1939, the first human bone marrow transfusion was completed. Post World War II, scientists strived to find ways to restore bone marrow function in aplasia patients caused by radiation exposure due to the use of the atomic bomb. It was proven in the 1950s in a mouse that bone marrow aplasia due to radiation can be fixed by a syngeneic marrow graft. Further tests were performed and published on two groups of mice with acute leukemia, where both groups were irradiated as anti-leukemic therapy as well as saved from marrow aplasia through bone marrow transplantation. These experiments demonstrated three major principles of hematopoietic stem cell transplants: “the role of the preparative anti-leukemic regimen in hematopoietic stem cell transplants, the ability of the new engrafted immune system to prevent leukemia relapse, and the activity of the engrafted immune system against the recipient”.

E. Donnall Thomas developed methods to identify and type human leukocyte antigens to allow for donor and recipient matching in the mid to late 1960s. Later on in 1979, he reported a 50% cure rate in acute myeloid leukemia patients in first remission; he then went on to win the Nobel Prize in 1990 for his contributions and discoveries in stem cell transplantation in the treatment of human diseases. In more recent years, more research has been put in place to aid in the development of stem cell transplantation. The International Bone Marrow Transplant Registry was created in 1972 for documenting hematopoietic stem cell transplant outcomes.

With constant research on the use of stem cells in the treatment of diseases, mesenchymal stem cells have also been studied for their potential therapeutic use in immune-mediated diseases. Bone marrow-derived mesenchymal stem cells have immense potential in the treatment of diseases because they are easily accessible in humans and the isolation of these stem cells is relatively straightforward yet holds the ability to expand rapidly in a short period of time. Mesenchymal stem cells have been shown to treat numerous diseases of the liver, lungs, pancreas, and kidney. Because mesenchymal stem cells differentiate into insulin-producing cells in vitro with pancreatic disorders, these cells hold great potential for the treatment of Type 1 diabetes. Mesenchymal stem cells are thought of as relatively safer and more feasible in the preservation of beta-cell function. One downside of these cells, however, is the discrepancy between the observed recovery of pancreatic islet cells and the low functionality of integration of donor mesenchymal stem cells. Furthermore, mesenchymal stem cells can be preserved with a minuscule loss of potency for on-site delivery and their human trials have so far shown no adverse reactions to autologous versus allogeneic transplants. This widens the availability in the clinical trials of mesenchymal stem cell treatments in cardiovascular, neurological, and immunological diseases. Despite these promising characteristics, mesenchymal stem cells still need to be studied and understood more. Initially, mesenchymal stem cells were thought to be stromal progenitor cells in the bone marrow with only one undifferentiated function of replenishing stromal tissue. Now, however, these stem cells are known for several other functions in bone marrow, which supports hematopoiesis.

One interesting source for mesenchymal stem cells has been found through hair follicles. These cells are readily accessible and can serve as a prime source of autologous stem cells for gene therapy in the treatment of Type 1 diabetes. In one study, mesenchymal stem cells were isolated from human hair follicles and then used to express the insulin gene. As a result, these cells were shown to be effective in releasing insulin in a manner that was dependent on time and dosing. Another source of mesenchymal stem cells is from adipose tissue. Adipose-derived stem cells possess a strong potential for proliferation, show low immune rejection, and have multiple differentiation capacities. These cells have been reported to treat Type 1 diabetes because they are a good source of autologous stem cells and possess specific surface markers, such as CD73 and CD90, which can bring about prolonged incubation time and strong proliferative capacity. Also, these adipose-derived stem cells can reduce inflammation of cell infiltration and improve the expression of insulin in the pancreas.

Early observations made by Cohnheim and Maximow in the early twentieth century served as the first indications of stromal cells in bone marrow involved in the body’s healing process and hematopoiesis. In the 1960s, in vivo transplantations of the bone marrow showed that these stromal precursors are vital in the formation of skeletal tissue cells. The method of isolating stromal cells from whole bone marrow based on differential adhesion to tissue culture plastic is still used today to separate mesenchymal stem cells and was first demonstrated by Friedenstein and his research team. These cells were adherent, clonogenic, fibroblastic, and nonphagocytic with the ability to produce colony-forming fibroblastic units. Later in the 1980s, Arnold Caplan hypothesized that there was a subpopulation of bone marrow stroma linked to mesenchymal tissues that were studied during chick embryogenesis. This eventually led to the coined term of “mesenchymal stem cells” to describe marrow stromal cells that are involved in melanogenesis. In more recent years, mesenchymal stem cells have been studied for their pleiotropic functions that aid in disease treatment. One problem, however, has existed in studying mesenchymal stem cells: the identification of a single marker that indicates a purified population of mesenchymal stem cells.

Currently, there is progress in stem cell therapy for treating Type 1 diabetes mellitus. Known in these research articles as T1DM, Type 1 diabetes mellitus is the most common chronic autoimmune disorder in young patients. With this type of diabetes, insulin deficiency and hyperglycemia result from the loss of pancreatic beta cells. As mentioned, pancreas and islet cell transplantation have evolved as promising new treatments for Type 1 diabetes by reconstructing the natural regulation of blood glucose in patients. That being said, there is a shortage of available donor pancreas and islet cells taken from human organ donors. These transplantations also pose complications, high costs, and have limited procedural availability. Stem cell therapy is, therefore, being greatly considered and developed for the treatment of Type 1 diabetes. Current research strategies utilize obtaining insulin-producing cells (IPCs) from various precursor cells.

Diabetes mellitus (DM) includes a wide range of chronic metabolic disorders involving hypoglycemia due to lack of secretion of insulin, or even insulin resistance. There are four main categories of diabetes mellitus: Type 1 diabetes mellitus (T1DM), Type 2 diabetes mellitus (T2DM), gestational diabetes, and monogenic diabetes. Type 1 diabetes requires daily insulin injections because of the insufficiency of endogenous insulin due to the body’s autoimmune destruction of pancreatic beta cells. This is why Type 1 diabetes is known as insulin-dependent diabetes mellitus. Type 1 diabetes destroys beta cells as the disease progresses, which makes it difficult to study these effects. Hypoglycemia, diabetic ketoacidosis, and hyperosmolar nonketotic coma (HHNC) are acute complications that can be caused by diabetes. Cardiovascular disease, diabetic nephropathy, and diabetic retinopathy are long-term, more serious complications associated with diabetes. The ideal treatment for diabetes requires the restoration of insulin production as well as insulin secretion regulation by glucose in diabetic patients. Therefore, clinical pancreas or islet cell transplantations have been viable treatment options for Type 1 diabetes patients with poor glycemic control. In 1966, Dr. Richard Lillehei successfully performed the first pancreas transplantation. According to the International Pancreas Transplant Registry, more than 50,000 patients around the world up until 2015 had received pancreas transplantations, while the first islet cell transplantation was performed in 1974. However, challenges in islet cell transplantation arise due to limited islet cell availability from donors as well as immune rejection. It was reported in 2000 that seven patients with Type 1 diabetes received sustained insulin independence from treatment with glucocorticoid-free immunosuppression along with the infusion of islet mass. Rigid glycemic control and correction of glycated hemoglobin levels were seen in all seven of these patients. This treatment method became known as the Edmonton protocol and has resulted in continuous improvements in islet isolation as well as immunosuppression over the past two decades. This has increased the efficiency of pancreatic islet transplantations, and about 60% of patients with Type 1 diabetes mellitus have been able to achieve insulin independence 5 years after their islet transplantation. However, there is a worldwide shortage of pancreas donors in clinical islet transplantations that poses a challenge for these procedures. Many studies of IPCs or islet organoids in vitro have been performed since human pluripotent stem cells (hPSCs) have been anticipated for use in regenerative medicine. Human embryonic stem cells (hESCs), human induced pluripotent stem cells (hiPSCs), adult stem cells, and differentiated stem cells from mature tissues that can be differentiated into IPCs are the main sources for the generation of IPCs or islet organoids in vitro. The basis for these methods of generating IPCs are on mimicking the natural pancreas development. Therefore, the obtained IPCs are supposed to express certain biological markers of normal beta cells that identify an end differentiation. After implantation into diabetic patients or immunodeficient diabetic animals, in vitro-generated IPCs or islet cell organoids are expected to change blood glucose and make sufficient insulin and hopefully reverse hyperglycemia.

Embryonic stem cells are pluripotent cells that are isolated from the inner cell mass of a blastocyst when the embryo implants into the uterus. These cells possess infinite proliferative capacity and self-renewal, which give ESCs the ability to differentiate into multiple types of adult cells in vitro. Induced pluripotent stem cells (iPSCs) are reprogrammed for somatic cells, but also hold a similar capacity to proliferate and differentiate as ESCs. Therefore, human pluripotent stem cells provide an important platform for producing in vitro cells that can secrete insulin. While there are ethical concerns in the usage of ESCs, iPSCs are derived from adult somatic cells that have been programmed back into mimicking embryonic pluripotent states through Yamanaka factors. Previously, the methods to generate IPCs from hPSCs were done by imitating the in vivo development of the embryonic pancreas. The addition of various cytokines and signaling modulators to each stage of embryonic pancreatic development in order to activate or inhibit signaling pathways involved in the production of adult beta cells, the fate of hPSC cells is manipulated into the beta cell phenotype. Various studies have confirmed that human embryonic stem cells as well as human induced pluripotent stem cells have the ability to differentiate into insulin-producing cells. However, this can only be done by carefully allowing the low differentiation efficiency of protocols and polyhormonal features of beta-like cells. One recent breakthrough in this research in 2014 detailed a more in-depth procedure for generating mature and functional insulin-producing cells from human pluripotent stem cells that are comparable to beta cells found in the human body.

Patient-derived human induced pluripotent stem cells have shown promising advantages in diabetic patients. These iPSC cells are able to be produced as patient-specific, which provides several important benefits, such as overcoming immune rejection or mismatch as well as providing a platform for personalized disease investigation and treatment. Type 1 diabetes-specific induced pluripotent cells, DiPSCs, are able to resemble embryonic stem cells in gene expression as well as differentiate into pancreatic cell lineages. This research shows promise towards autologous stem cell treatments for pancreatic progeny transplantation for patients with Type 1 diabetes. Studies were done to transplant these cells in immunodeficient mice, and the engraft function was then evaluated by serum human insulin before and after an injection of glucose. Notably, after months of monitoring these insulin secretions, the human insulin content increased by about 1.5 times after glucose stimulation. After these studies, it is thought that epigenetic changes that result from dysmetabolism in Type 1 diabetic patients cause a decreased production of beta cells. One important issue, however, that needs to be addressed in human pluripotent stem cell-derived pancreatic progenitors is the effects a recipient’s in vivo environment has on the differentiation and maturation of the undifferentiated stem cells. Even further, interspecific chimeras are organisms with cells from at least two different species and are able to fully produce organs made up of donor-originating cells. This shows promise for human and animal chimeras as means for providing human transplantation organs that are patient-specific for those with Type 1 diabetes.

One promising feature of stem cell therapy in the treatment of Type 1 diabetes is human-derived beta cells. These cells would serve as a potential replacement for the beta cells that those with Type 1 diabetes are lacking. The autoimmune and alloimmune responses, however, exist as a major issue in the vast application of this method. The recipient’s immune system will destroy the engraftments put into place if the encapsulation process is not sufficient. However, specific models of the encapsulated cells have been designed to eliminate autoimmune attacks. Beta cells are very susceptible to stress, which could possibly play a role in the development of diabetes. In order to study this, in vitro stem cell beta-cells were subject to various chemical stressors, and then their persistence was studied through the co-expression of beta-cell markers. Several of these stress treatments reduced the expression of these factors, with a cytokine stress treatment holding the most destructive potential.

Since cytokines and inflammation play a large role in Type 1 diabetes, the effects of interleukin-1beta tumor necrosis factor-alpha and interferon-gamma were studied. These cytokine treatments resulted in a huge loss of both C-peptide cells that express NKX6-1 as well as those that express MAFA and PDX1. This reduction has been reported in patients with Type 1 diabetes, and it was hypothesized that Type 1 diabetic stem cell beta-cells would be more sensitive to this cytokine stress than nondiabetic stem beta-cells, yet no notable difference was observed. However, these reductions in response to cytokine stress can be reduced through treatment with Alk5i.

In recent years, many clinical trials have been performed to determine the efficiency and safety of stem cell treatment therapy for patients with Type 1 diabetes. Specifically, it has been proven that mesenchymal stem cells have the capability to reverse Type 1 diabetes in animal models afflicted with this disease. A study was performed in 2014 by Carlsson to confirm that mesenchymal stem cell treatment could maintain beta cell function in Type 1 diabetics. The study involved twenty adult patients who were newly diagnosed with Type 1 diabetes and followed up with after a year of mesenchymal stem cell treatment or no treatment in the control group. It was determined at the end of the trial period that C-peptide values significantly decreased in the treatment group and no effects of mesenchymal stem cell treatment were observed. Another study in 2009 and 2010 involved randomized patients to either receive stem cell treatment from umbilical cord mesenchymal stem cells in combination with autologous bone marrow cells or standard insulin treatment for Type 1 diabetes. After another 1-year follow-up period, C-peptide increased in treated patients and decreased in the control group, while insulin increased in treated patients and decreased in the control group. There was also a lesser need for daily insulin treatments in the treated group compared to the control group. Even though the sample sizes for these studies were small and hold promise for future clinical trials, more research needs to be completed to achieve satisfactory results. There are several major problems in achieving stem cell treatment for Type 1 diabetes, including generating functional beta cells in vitro, the differentiation efficiency of insulin-producing cells from human pluripotent stem cells, the protection of implanted insulin-producing cells from autoimmune attacks, the generation of satisfactory numbers of cell types for clinical treatment, and most importantly the establishment of insulin independence. All of these obstacles require more research in future years, but stem cell therapy holds the greatest potential for curing Type 1 diabetes.

Based on studies in sheep, it has been reported that human mesenchymal stem cells can form hepatocytes, cardiac and gastrointestinal cells, and human hemopoietic elements. Similarly, human hematopoietic stem cells possess the ability to generate long-term hepatic, hemopoietic, and beta cell activity post-transplantation in utero in sheep, human myelo, and lymphopoietic activity in mice. In vitro data supports the ability of stem cells to differentiate in beta-like cells capable of producing insulin through genetic or chemical manipulation. With these studies done in sheep or syngeneic mice, there is support for the differentiation of either hematopoietic stem cells or mesenchymal stem cells into fully functioning human beta-like cells.

Due to the increase of patients around the world with Type 1 diabetes, stem cell research in this area has been very prevalent in laboratories and research facilities. The transplantation of exogenous beta cells to replace dead or nonfunctional endogenous beta cells is a promising procedure for controlling blood glucose levels in patients with Type 1 diabetes. Cadaver allogeneic transplants of islet cells have been successfully performed on patients with Type 1 diabetes, but this procedure has a limited supply of islets and requires immunosuppressants for patients. There are several alternative strategies to islet transplantation due to the limited availability here. First, stem cells, either hematopoietic or mesenchymal, are being differentiated into endocrine pancreas cells and then transplanted either autologously or through allogeneic transplantation. Mesenchymal and/or hematopoietic stem cells are also being modulated to regenerate endogenous islet cells. Stem cell therapies involving hematopoietic stem cell-mediated gene therapy could eliminate the destruction of antigen-expressing islet cells through the termination of antigen-specific T-cell memory responses. Even further, in vitro models of mesenchymal stem cells transforming into insulin-producing cells are being done prior to transplantation, whether through an allogeneic or autologous donor. Also, mesenchymal stem cell co-transplantations are being used with intact islet cells in order to improve islet engraftment and eventual function. Lastly, in vitro embryonic stem cells are being differentiated into beta cells that are encapsulated in polymers in order to prevent rejection and then implanted into the peritoneum.