Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes

The generation of islet-like endocrine clusters from human pluripotent stem cells (hPSCs) has the potential to provide an unlimited source of insulin-producing β cells for the treatment of diabetes. In order for this cell therapy to become widely adopted, highly functional and well-characterized stem cell-derived islets (SC-islets) need to be manufactured at scale. Furthermore, successful SC-islet replacement strategies should prevent significant cell loss immediately following transplantation and avoid long-term immune rejection. This review highlights the most recent advances in the generation and characterization of highly functional SC-islets as well as strategies to ensure graft viability and safety after transplantation.

Insulin is an essential regulator of energy metabolism throughout the body, directing the usage of carbohydrates, fats, and proteins.1,2,3,4 In particular, the binding of insulin to cell surface receptors facilitates the entry of glucose from the blood stream into many cell types within the body, most notably in muscle and fat, so that they can use it as energy. Insulin signals for excess glucose to be stored for future use as glycogen in the liver and muscle as well as converted to fat in adipocytes. In parallel, insulin signaling slows the breakdown of fats and proteins, as they are not needed much when glucose is plentiful. The amount of insulin circulating in the blood changes dynamically in response to the constantly changing energy needs of the body and the availability of each fuel source. Specialized endocrine cells called β cells, located in the islets of Langerhans within the pancreas, are responsible for this tightly regulated production and release of insulin. After a meal, for example, blood glucose levels rise as carbohydrates are broken down into glucose and absorbed into the blood stream. β cells can rapidly sense this increasing blood glucose level and secrete the appropriate amount of insulin in response, allowing cells throughout the body to utilize this glucose for energy production. Blood glucose levels fall as glucose enters cells, causing the β cells to slow their release of insulin. This reduction in insulin secretion in conjunction with an increase of the counter-regulatory hormone glucagon by α cells prevents blood glucose levels from dropping below a set threshold (∼70 mg/dL in humans), as a minimum concentration is required for tissues of the central nervous system to function properly. By rapidly changing the amount of insulin and glucagon in circulation, β and α cells maintain blood glucose levels in a narrow optimal range.
In type 1 diabetes (T1D), β cells are selectively destroyed by an autoimmune process, resulting in the inability to produce and secrete insulin.5,6 Without insulin, glucose homeostasis and energy metabolism balance in the body are completely disrupted. As many cell types can no longer import glucose for energy, they must switch to metabolizing free fatty acids that are liberated from the breakdown of triglycerides in adipocytes as their main energy source. Importantly, as the liver processes free fatty acids, it generates ketones that can also be used as an energy source by other tissues. While this process is normal during periods of fasting and low-carbohydrate dieting, the complete absence of insulin signaling in T1D results in uninhibited fat breakdown and uncontrolled ketone production. The rapid buildup of ketones changes blood pH, resulting in the life-threatening condition called ketoacidosis.7,8 Thus, patients with T1D must inject exogenous insulin in order to survive and restore the necessary signaling pathways that properly regulate their energy metabolism.

While injecting insulin allows T1D patients to stay alive, replicating the precise insulin secretion dynamics of β cells can be difficult. Not only do patients need to consider what they are eating when calculating an insulin dose, but because insulin requirements are intimately linked to energy metabolism, other factors such as the intensity and duration of physical activity as well as stress levels can influence how much insulin the body requires at a given time. Incorrectly estimating the amount of insulin needed at a particular time can create both short and long-term issues. For example, not giving enough insulin will cause the blood glucose level of a patient to be higher than it should be. In the extreme, high glucose levels can change blood osmolarity and result in life-threatening dehydration.8 Moderately high glucose levels are not a serious issue in the short term, though they may make the patient feel suboptimal. Over the lifetime of the patient, however, this chronic elevation of blood glucose concentration can damage tissues throughout the body. Therefore, it is critically important to try to keep blood glucose levels as close to normal as possible to avoid long-term complications, such as cardiovascular, kidney, and eye diseases.9,10 On the other hand, giving too much insulin is dangerous in the short term because it can cause blood glucose levels to dip below the normal lower limit. The central nervous system requires a constant supply of glucose to function, and a certain concentration in the blood is required to facilitate sufficient transport of glucose across the blood-brain barrier.11 Thus, as blood glucose levels drop below this threshold, a person can start to act abnormally as their brain essentially starves. If blood glucose levels continue to fall, the person can lose consciousness and ultimately die.12 Consequently, patients taking insulin must try to navigate between these two extremes and estimate the amount of insulin their body needs based on their current metabolic state.

The treatment of T1D has made great strides in recent years. In particular, new tools such as insulin pumps and continuous glucose monitors have undoubtedly made living with diabetes easier and have helped many patients achieve better control over their blood glucose levels.13 Despite these advances, however, many patients still fail to achieve their target goals. Moreover, even if they do meet their blood glucose targets, the therapy can remain burdensome, as it still requires constant monitoring and adjustment. Because of the difficultly in replicating the precise insulin secretion dynamics of β cells with exogenous insulin injections, a potentially better treatment alternative consists of replacing the lost β cells with new ones, allowing these transplanted cells to monitor blood glucose levels and secrete the appropriate amount of insulin in response. Such a transplant would provide a “functional cure” for T1D patients, as they would no longer have to manage their blood glucose levels with insulin injections. Type 2 diabetics who rely on insulin injections may also benefit from such a transplant. Intriguingly, T1D is a potentially ideal candidate for cell replacement therapy. Because individual β cells can sense extracellular glucose changes and secrete insulin, there is less of a need for a complex working structure of multiple integrated cell types, as would be required in tissue engineering whole organs such as a heart or kidney. Rather, as long as the β cells secrete insulin properly in response to glucose stimulation and are transplanted in a location that facilitates adequate exchange of these molecules with the blood stream, such a cell replacement therapy could provide a functional cure for T1D.