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The mechanism of stem cell transplantation in treatment of diabetes mellitus
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The main mechanism and research status of stem cell transplantation in the treatment of diabetes mellitus.
The ideal treatment for diabetes is to improve peripheral insulin resistance and promote pancreatic β-cell regeneration. Stem cell therapy is the most promising approach to compensate and restore the function of insulin-secreting pancreatic beta cells.
Diabetes mellitus (DM) has become one of the major public health care problems worldwide in recent decades. In 2017, it was reported that about 425 million adults worldwide had diabetes, and it is estimated that by 2045, the number of diabetic patients may reach 629 million.
Diabetes is characterized by high morbidity and mortality in adult patients, and is also a major risk factor for cardiovascular and other diseases. In addition, it can also induce complications in different organs such as retinopathy, neuropathy and end-stage renal disease , causing serious harm to people’s life and health.
- Type 1 diabetes: caused by insufficient insulin secretion. The more common situation is that the body produces antibodies against islet beta cells. Due to the attack of these antibodies, islet beta cells cannot effectively secrete insulin.
- Typical symptoms are: polydipsia, polyuria, polyphagia, and weight loss . It occurs mostly in children and adolescents, but can also occur at various ages.
- Type 2 diabetes: T2DM is an age-related metabolic disease caused by peripheral tissue insulin resistance and insulin-secreting pancreatic β-cell dysfunction, accounting for 90% to 95% of all diabetes cases.
- Typical symptoms are: fatigue, weakness, obesity and so on . Type 2 diabetes is more common among people over 45 years old, but type 2 patients are also getting younger. Genetic background, obesity and physical inactivity are common risk factors for developing type 2 diabetes.
Current treatments for diabetes typically include oral and injectable antidiabetic drugs that reduce hyperglycemia or temporarily improve insulin sensitivity in target tissues, but they neither reverse insulin resistance nor the progressive and inevitable beta-cell dysfunction .
The ideal treatment for diabetes is to improve peripheral insulin resistance and promote pancreatic β-cell regeneration. Compensating and restoring the function of insulin-secreting pancreatic beta cells is the most promising approach. This approach controls blood sugar levels and regenerates insulin-secreting beta cells from adult cells.
Based on the above principles, mesenchymal stem cells (MSCs) from different adult tissues have attracted great attention in the treatment of diabetes in recent years.
What are mesenchymal stem cells?
Stem cells are the origin cells of the body and the progenitor cells that form various tissues and organs of the human body. Mesenchymal stem cells belong to a class of pluripotent stem cells in the mesoderm , with strong proliferation ability and multi-directional differentiation potential, and are an important research branch of stem cells. According to the registration of Clinical Trials, there are nearly 10,000 clinical studies on mesenchymal stem cells worldwide.
Mesenchymal stem cells are stromal-derived non-hematopoietic progenitor cells derived from various tissues of adults and neonates , such as bone marrow (BM), umbilical cord (UC), umbilical cord blood (UCB), placenta, dental pulp and skin, etc. can expand. It is worth noting that the biological properties of MSCs from various sources are different.
According to the frequency of colony formation, expansion characteristics, multi-directional differentiation ability, immunophenotype and paracrine function of mesenchymal stem cells obtained from different sources, different clinical applications can be determined.
Mesenchymal stem cells possess pluripotency, self-renewal capacity, and the ability to modulate immune responses, and therefore, are considered potential therapeutic agents for the treatment of many diseases and regeneration of damaged tissues. For example, induction of MSCs into insulin-secreting cells (IPCs) promotes pancreatic regeneration and alleviates insulin resistance, providing an alternative to islet cell transplantation in the treatment of diabetes.
The main principle of stem cell transplantation in the treatment of type 2 diabetes mesenchymal stem cells directed transdifferentiation into IPCs in vitro
It is now generally believed that the main mechanism of using mesenchymal stem cells to improve hyperglycemia in type 2 diabetes is its potential to differentiate into IPCs.
After extensive experimental studies, researchers have proposed a multi-step protocol for the differentiation of MSCs from different sources into IPCs. And the glucose tolerance test revealed that the differentiated IPCs produced insulin through a glucose-regulated physiological signaling pathway.
Mesenchymal stem cells promote islet beta cell regeneration
In addition to differentiating into IPCs, MSCs can also migrate to damaged islet cells, secrete a variety of cytokines and growth factors with paracrine and autocrine activities to participate in the repair of islet cells, thereby promoting the regeneration of islet β cells. MSCs can also promote the transdifferentiation of islet α cells to β cells.
Immunological properties of mesenchymal ste0m cells
MSCs have low immunogenicity and immunomodulatory properties, which can protect pancreatic β cells and reduce damage caused by autoimmunity.
Numerous studies have shown that MSCs have immunomodulatory or immunosuppressive effects on several immune cells [not only T lymphocytes, but also B lymphocytes, dendritic cells (DC) and natural killer (NK) cells] both in vitro and in vivo. .
In vitro studies have established that MSCs exert immunomodulatory functions through cell-cell contacts and soluble factors. MSCs inhibit the secretion of pro-inflammatory cytokines by secreting soluble anti-inflammatory factors such as interleukin-10 (IL-10), transforming growth factor-β (TGF-β) and human leukocyte antigen-G (HLA-G). This inhibits immune cell proliferation and transforms the immune cell type into a regulatory clone.
These properties make MSCs promising as a new alternative therapy for autoimmune diseases such as type 2 diabetes.
The latest clinical research progress of stem cell therapy for diabetes
In recent years, stem cells have achieved promising results in many types of diabetes clinical trials. As of March 29, 2022, the National Institutes of Health (ClinicalTrials.gov) included 135 clinical trials of stem cells for the treatment of diabetes .
A number of clinical studies on type 1 diabetes and type 2 diabetes have shown that stem cells are effective and safe in the treatment of diabetes, and have initially achieved relatively good results.
A case study of stem cell transplantation in the treatment of type 1 diabetes
As early as 2012, the Drum Tower Hospital Affiliated to Nanjing University School of Medicine published the results of a clinical trial in J Clin Endocrinol Metab. It’s called diabetic ketoacidosis. The experimental results show that autologous hematopoietic stem cell transplantation can regulate immune-competent cells and improve the function of beta cells.
Efficacy and safety of autologous hematopoietic stem cell transplantation in the treatment of new-onset type 1 diabetes
In the same year, a clinical study reported by Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine showed that autologous hematopoietic stem cells could completely stop exogenous insulin in 15 of 28 patients with type 1 diabetes (53.6%) by improving pancreatic β-cell function. , the clinical remission rate of patients without ketoacidosis at onset was higher than that of patients with ketoacidosis at onset.
In 2017, the Second Xiangya Hospital of Central South University was the first in the world to use the “Stem Cell Education Therapy” for the treatment of children with type 1 diabetes. Adolescents from China, the United States, Spain, Australia and other countries received treatment.
After treatment, their insulin dosage was reduced and the decline rate of C-peptide was slower than that of the control group. Some even completely got rid of insulin during the 15-month follow-up period. treat.
Clinical research case of stem cell transplantation in the treatment of type 2 diabetes
In the treatment of T2DM, 10 patients were found to have improved renal and cardiac function after transplantation of placenta-derived MSCs, and the average daily dose of insulin was also reduced  . In addition, studies on WJ-MSCs also confirmed the improvement of metabolic control and β-cell function  .
In another study, UCB-MSCs were injected into the dorsal pancreatic artery of three T2DM patients with different history of diabetes mellitus through microcatheter, and the C-peptide level of the patients was increased, and the requirement for insulin was decreased .
To explore how the route of administration affects the clinical efficacy, Sood et al.  injected autologous skeletal MSCs into 21 patients through the pancreaticoduodenal artery, splenic artery and peripheral vein, respectively.
The results showed that there was no discernible homing in the IV group and no significant change or improvement in clinical outcomes.
This method is ineffective in T2DM patients. The pancreatoduodenal artery group had the most obvious homing effect, and the insulin dose requirement of the target patients was significantly reduced.
This demonstrates that the delivery of stem cells to the pancreas is an important prerequisite for achieving therapeutic efficacy.
On the other hand, in clinical studies, there is a direct relationship between the injection dose used for stem cell therapy and the therapeutic effect.
Recent studies have also confirmed the dose-response relationship of allogeneic BM-MSCs in the treatment of T2DM. After treatment with 0.3 × 106 ~ 2.0 × 106 cells/Kg MSCs, injection of higher doses of stem cells showed better therapeutic effect  ]. At all time points, higher doses of MSCs were associated with greater reductions in HbA1c levels compared to placebo.
Challenges and Future Prospects of Stem Cell Therapy for Diabetes
A large number of studies have shown that mesenchymal stem cells have great potential in the treatment of type 2 diabetes. However, there are still many obstacles to overcome.
① First, we need to establish a standardized production process for mesenchymal stem cells, including the source, culture medium, and passage of mesenchymal stem cells.
②How to establish a high-efficiency MSCs expansion system to meet clinical needs while maintaining high expansion and transdifferentiation potential needs further research.
③Secondly , the administration route, dose, administration interval and frequency of mesenchymal stem cells need to be continuously optimized to obtain the best treatment plan.
④ At the same time, we will continue to explore new MSCs therapies, such as the application of mesenchymal stem cell-derived exosomes to the treatment of type 2 diabetes .
To sum up, with the continuous deepening of research and the continuous maturity of clinical technology, it is believed that the bright prospect of stem cell therapy for diabetes will be more widely confirmed, and bring rebirth to patients suffering from diabetes.
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J Clin Endocr Metab 2013; 98(9): E1501.
World J Diabetes 2017; 8(7): 381-9.
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The main mechanism and research status of stem cell transplantation in the treatment of diabetes mellitus.
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