Cell, an international authoritative scientific journal, recently published a pioneering achievement from multiple research teams in China - the first time to use stem cell regeneration therapy to functionally cure type 1 diabetes. The research team used chemical reprogramming technology to induce pluripotent stem cells to prepare islet cells, and transplanted them to a type 1 diabetes patient, achieving clinical functional cure effect.
So, how is it successful to induce stem cells to prepare pancreatic islet cells? Is functional cure truly a cure? Will stem cell technology be the key to conquer diabetes in the future?
What is the difference between functional cure and cure

Diabetes is a thorny disease, and its biggest harm to patients is that there are many clinical complications, which may lead to cardiovascular disease, nervous system damage, kidney disease, eye disease, foot disease, and so on.
Diabetes ranks ninth among the world's ten leading causes of death and disability recently announced by the world health organization. Last year, the Lancet published online a research result of the global burden of disease, estimated the global burden of diabetes from 1990 to 2021, and predicted the global situation of diabetes in 2050. The latest statistics show that there will be 529 million diabetes patients in the world in 2021, and the age standardized incidence rate of diabetes (the incidence rate after removing age influencing factors) in the world will be 6.1%. It is estimated that by 2050, there will be 1.31 billion diabetes patients worldwide, including about 485 million diabetes patients among people aged 20 to 79. Globally, the age standardized incidence rate of diabetes in men (6.5%) is higher than that in women (5.8%).
According to the data of the International diabetes Alliance, as of 2021, China has 141 million diabetes patients aged 20 to 79 years old, making it the largest country with diabetes in the world. Such a large number of patients means that it is very important to pay attention to the treatment of diabetes. The classification of diabetes is based on pathology, including four major types: type 1 diabetes, type 2 diabetes, pregnancy diabetes and other special types of diabetes. The first three are the main types, and their treatment needs to be different according to different pathology. However, the mechanism of the immune system attacking the β cells that produce insulin and the mechanism of the body's tolerance to insulin are still not completely clear, so the type 1 and type 2 diabetes that trouble most people are difficult to cure.
This time, researchers from three regions in China have made new attempts and achieved the result of "clinical functional cure". This joint research team includes the research groups of Shen Zhongyang and Wang Shusen from Tianjin First Central Hospital, Deng Hongkui from Peking University and Changping Laboratory, and Hangzhou Ruipu Chenchuang Technology Co., Ltd. Researchers use chemically induced pluripotent stem cells to prepare islet cells, and these islet cells can secrete insulin, thus solving the cause of type 1 diabetes patients unable to produce insulin from the source. In this study, a patient with 11 years' history of type 1 diabetes who was completely dependent on insulin treatment but had poor blood glucose control was treated by transplanting islet cells prepared by chemically induced pluripotent stem cells. After receiving transplantation, patients regained endogenous autonomy and physiological blood glucose regulation, achieving a functional cure effect.
What is functional cure? Functional cure is a concept second only to complete cure, also known as clinical cure. It was first used to cure chronic infectious diseases such as AIDS or chronic hepatitis B, that is, after the disease has passed treatment and stopped treatment, it will no longer show clinical symptoms. At the same time, the existing detection technology cannot detect the pathogen that causes the disease in the human body.
Taking chronic hepatitis B as an example, complete cure means that after a period of treatment, hepatitis B B surface antigen in serum cannot be detected and hepatitis B virus DNA is cleared. The functional cure means that the hepatitis B virus in the infected person is completely suppressed and the immune function of the body is normal. Even without treatment, it is difficult to detect hepatitis B B surface antigen and hepatitis B virus DNA in the blood with conventional methods. In other words, although functional cure cannot completely eliminate viruses from the body, it can delay or reduce the occurrence of decompensated cirrhosis, liver failure, and hepatocellular carcinoma, thereby improving the quality of life and prolonging survival time of patients.
Similarly, although functional cure of type 1 diabetes cannot completely solve the cause of type 1 diabetes that cannot produce insulin, it can keep the body at a normal blood sugar level and restore normal blood sugar supply. Even without the use of drugs, diabetes symptoms will not occur, and the complications of diabetes can be delayed and reduced.
How stem cells transform into pancreatic islet cells

Speaking of the pluripotent stem cells that played a key role in the research achievements in China, they are cells that can differentiate and develop into various tissues and organs, including all cells from fertilized eggs to 32 cells before cleavage. To differentiate stem cells into functional cells with various functions, such as pancreatic islet cells, stem cells need to be programmed.
In 2006, Japanese scientist Shinya Yamanaka and her colleagues discovered that adult mouse fibroblasts could be transformed into induced pluripotent stem cells by introducing four transcription factors (Sox2, Oct4, KLF4, and c-Myc). For this, he and British scientist John Gordon jointly won the 2012 Nobel Prize in Physiology or Medicine. The discoveries of these two scientists laid the foundation for regenerative medicine. However, there are some practical issues with using genetically modified transcription factors to transform adult cells into pluripotent stem cells. For example, gene regulation cannot be accurately controlled, uncontrollable genetically modified organisms may also induce cancer, and so on. Therefore, in order to induce pluripotent stem cells with practicality, there are still many technical issues that need to be addressed.
Deng Hongkui's research team in China has explored a feasible way to make pancreatic islet cells from pluripotent stem cells, and then transplant the latter into patients to produce insulin to treat diabetes. This requires addressing several key technologies: firstly, how to obtain human pluripotent stem cells; The second is how to induce pluripotent stem cells to prepare pancreatic islet cells; The third is how to transplant pancreatic islet cells into the human body.
In 2013, Deng Hongkui's team created a way to convert fibroblasts into induced pluripotent stem cells using chemical small molecules, called chemically induced pluripotent stem cells (CiPSC), which have functions in fertile mice. Subsequently, Deng Hongkui's team revealed the molecular pathways for generating chemically induced pluripotent stem cells in 2015 and 2018, respectively.
Then, in 2022 and 2023, Deng Hongkui's team created the human chemically induced pluripotent stem cell (hCiPSC) technology, and proved that this technology can prepare islet cells and produce insulin, and can improve the diabetes of non-human primates. For this reason, Deng Hongkui has been awarded the "Life Science Award" in China's 2024 Future Science Awards, in recognition of his outstanding contributions in using chemical methods to reprogram somatic cells into pluripotent stem cells, altering cell fate and state.
Finding a 'good location' for islet cell transplantation

How to transplant pancreatic islet cells into the human body after preparing them from pluripotent stem cells? Deng Hongkui's team has collaborated with other teams to create a new transplantation method, which involves transplanting pancreatic islet cells into the anterior sheath of the rectus abdominis muscle.
In the past, donor islet cells or human derived islet cells transplantation was also used for type 1 diabetes. Liver portal vein transplantation was commonly used, and the transplanted islet cells were permanently implanted in the liver. James Shapiro's team from the University of Alberta in Canada created an Edmonton scheme for treating type 1 diabetes in the 1990s - to transplant islet cells into the liver, so that patients do not need to inject insulin again. Although this therapy was hailed as a revolutionary treatment option at the time, clinical practice has proven that the liver is not an ideal site for transplanting pancreatic islet cells, as there is a high risk of bleeding and coagulation when transplanted into the portal vein of the liver, and most pancreatic islet cells undergo inflammatory reactions within minutes to hours, leading to massive death. In addition, transplanted pancreatic islet cells are scattered throughout the liver, making it difficult to track and observe, and cannot be removed.
The Shapiro team tested another ideal location for transplanting pancreatic islet cells - subcutaneously, but it was still not ideal because the subcutaneous tissue lacked the blood vessels needed for pancreatic islet cell growth and reproduction. Afterwards, the team implanted a temporary catheter subcutaneously as a blood vessel that could induce cell growth, creating an environment for pancreatic islet cell transplantation.
The above situation made Deng Hongkui's team realize the need to adopt new methods to address the safety and effectiveness of pancreatic islet cell transplantation, especially for pancreatic islet cells prepared from human chemically induced pluripotent stem cells, which require suitable transplantation sites.
For this purpose, they explored a new surgical technique of transplanting pancreatic islet cells under the anterior sheath of the rectus abdominis muscle. Research has shown that this method of transplantation poses no risk of bleeding or coagulation, and the surgery is simple and can be completed under ultrasound guidance. Moreover, the transplanted pancreatic islet cells are confined to a specific space under the anterior sheath of the rectus abdominis muscle, and imaging techniques can be used to monitor and control the transplant. Compared with other extraperitoneal transplantation methods such as subcutaneous transplantation and intramuscular transplantation, rectus abdominis anterior sheath transplantation can effectively support the early survival and long-term maintenance of pancreatic islet cells prepared from human chemically induced pluripotent stem cells.
The researchers infused islet cells prepared by human chemically induced pluripotent stem cells into the anterior sheath of rectus abdominis of type 1 diabetes monkeys, and the blood glucose control of all diabetes monkeys who received transplantation was significantly improved. Twelve weeks after transplantation, the glycosylated hemoglobin value of diabetes monkeys decreased by an average of 44%, reaching the level of healthy monkeys. The amount of exogenous insulin used to control blood sugar decreased by 43%. At the same time, after transplantation of pancreatic islet cells prepared from human chemically induced pluripotent stem cells, the endogenous insulin secretion level is significantly increased and can respond to changes in blood glucose concentration.
These results prove that transplantation of islet cells prepared by human chemically induced pluripotent stem cells under the sheath of rectus abdominis muscle can make islet cells survive efficiently, gradually acquire mature function in vivo and maintain its physiological function for a long time, thus curing type 1 diabetes.
Open up new paths for the widespread application of cell therapy

On the basis of the above research achievements, the Chinese research team carried out the transplantation treatment of islet cells prepared by autologous human chemically induced pluripotent stem cells in a patient with type 1 diabetes with an 11 year history on June 25, 2023. Previously, the patient's "sugar control" journey was very difficult. Despite intensive insulin therapy, blood sugar could not be effectively controlled. The pancreatic transplant surgery they underwent was declared a failure one year later, and the group reactive antibody was strongly positive. This is an antibody against human leukocyte antigen, which is not conducive to organ transplantation.
After receiving transplantation therapy using human chemically induced pluripotent stem cells to prepare pancreatic islet cells, the patient's multiple clinical efficacy key data are encouraging, mainly manifested in two aspects. Firstly, the patient's fasting blood glucose level gradually returned to normal, and the need for exogenous insulin injection therapy continued to decrease. From the 75th day after transplantation, complete and stable detachment from insulin injection therapy was achieved. As of the publication of the research paper in the journal Cell, the patient had been off insulin therapy for over a year. Secondly, the level of glycated hemoglobin decreased to 4.76% one year after transplantation. The detection result of glycosylated hemoglobin level can reflect the average blood sugar level in the past two to three months. If the glycosylated hemoglobin level exceeds 6.5%, diabetes can be diagnosed; Between 5.7% and 6.4%, it can be diagnosed as pre diabetes; If it is below 5.6%, it is considered normal.
The final results showed that transplantation of islet cells prepared by human chemically induced pluripotent stem cells under the anterior sheath of rectus abdominis muscle could cure diabetes functionally.
In fact, this transplantation technique belongs to the category of regenerative medicine. Regenerative medicine is a cutting-edge interdisciplinary field that utilizes principles and methods from disciplines such as life sciences, materials science, clinical medicine, computer science, and engineering to study theories and techniques for replacing, repairing, rebuilding, or regenerating various tissues and organs in the human body. Among them, the most commonly used approach is to repair damaged or diseased tissues and organs in the human body through the regenerative and reparative effects of stem cells.
Stem cells are a type of cell with self-renewal ability and multipotent differentiation potential, which can differentiate into various functional cells, tissues, or organs under specific conditions. During the developmental stage, stem cells are divided into two categories: embryonic stem cells and adult stem cells. According to their developmental potential, stem cells can be divided into three categories: pluripotent stem cells, pluripotent stem cells, and pluripotent stem cells.
Gene editing and chemical induction of adult stem cells can induce their differentiation into specific cells. The islet cells prepared by human chemically induced pluripotent stem cells mentioned above are one of them. Transplanting such cells to patients with type 1 diabetes can achieve functional cure of diabetes.
At present, the differentiation of stem cells into specific cells and tissues through biological and chemical methods can be used to treat various diseases, including spinal cord injury, Parkinson's disease, ALS, Alzheimer's disease, heart disease, stroke, burns, cancer, and osteoarthritis. The functional cells prepared by Chinese researchers using chemical reprogramming technology have achieved initial success in the clinical treatment of diseases, indicating that chemical reprogramming is expected to become a universal underlying technology for efficient preparation of various functional cell types in the future, opening up a new path for the widespread application of cell therapy in the treatment of major diseases. (Zhang Tiankan)