Type 1 diabetes (T1D) is a chronic metabolic disease that is characterized by low insulin production and hyperglycemia due to the autoimmune destruction of insulin-secreting pancreatic beta (β) cells. Diabetes causes severe chronic complications with irreversible multi-organ damage in patients. In particular, these complications are diabetic nephropathy, neuropathy, retinopathy, and cardiovascular diseases. Diabetic nephropathy (DN) led up to 40% of end- stage renal disease (ESRD) cases worldwide, and up to 70% of T1D deaths are due to cardiovascular events, which are 10 times more common in patients with diabetes than healthy people.

Approximately, 85% of cases of T1D occurred in people under the age of 20 years, wherein the impairment of glucose homeostasis and diabetes complications drastically decreases the patients’ life expectancy and quality of life. The process of autoimmune destruction of insulin- secreting cells starts in genetically https://www.nih.gov/news-events/nih-research-matters/encapsulated-cells-treat-diabetes-mice predisposed individuals under the triggering effects of one or more environmental factors (such as virus diseases, nutritional factors, gut microbiome changes, and obesity). Prior to the T1DM clinical manifestation, a β-cell apoptosis within the islets of Langerhans occur with the participation of T lymphocytes with the predominant cell type being CD8+ T cells, macrophages, B lymphocytes, and dendritic cells. The subpopulation of T regulatory lymphocytes (or suppressive lymphocytes) needed for peripheral tolerance has quantitative and qualitative deficits in T1D patients, which may explain the abnormal immune response and autoimmune process development. As such, immune cells and their secretory factors, including pro-inflammatory cytokines, make an inflammatory environment that gradually mediates β-cell death. T1D could progress over a period of many months to years without any symptoms; however, the abundant islet cell death has already occurred through this time. Symptomatic hyperglycemia is developed after this long latency period because the large number of β cells that were already destroyed by the immune system could not produce enough insulin. This means, a pathological process has already appeared and developed in the body long before T1D would be revealed. As a result, it is very important to diagnose this autoimmune disorder as early as possible, ideally before T1D manifestation. Likewise, it was shown that during asymptomatic and euglycemic periods, blood tests will be positive for relevant autoantibodies. Almost all patients with T1D have antibodies to multiple islet autoantigens simultaneously. The data on measuring autoantibodies GADA, IA-2A, IAA, and ICA (ZnT8A) in blood of patients with T1D showed that only 2–4% of patients are autoantibody negative, fewer than 10% have only one positive test for antibodies, and around 70% have three or four markers.

There is a prospective investigation for risk of T1D development for genetically predisposed children after islet autoantibody positive tests r esults during a 10- year follow-up. For 585 children with multiple islet autoantibodies, this risk of T1D occurring was estimated as 69.7% (95% CI, 65.1%-74.3%); and for 474 children with a single islet autoantibody, it was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes occurrence in children who had no islet autoantibodies was only 0.4% (95% CI, 0.2%-0.6%) at the age of 15. Thus, “multiple antibody positivity” is suitable for T1D diagnosis and for predicting diabetes early in individuals without symptoms. Early diagnosis could increase the efficiency of different immunotherapies to slow down β cells death rate and prevent serious complications.

To date, exogenous insulin administration is the most common and life-saving treatment option for T1D that relies on the control of circulating glucose as tightly as possible. However, it is not a cure for the disease as insulin administrations could not substitute normal pancreatic islet function and provide accurate glucose control over time. Mechanical and biologic insulin delivery systems with varying levels of accuracy are still constantly under development to overcome this issue. So, if the maintenance of tight glycemic control along with insulin regimen is unsustained, hypoglycemic episodes will occur with severe secondary complications that shorten the patient’s life span. As follows, exogenous insulin administration cannot prevent the progressive degeneration of islet β-cells and thus disease progression.

Relatively, islet cell transplantation and pancreatic transplantation are treatments directed to β-cells mass regeneration. These therapy strategies are effective but limited by the donor’s lack of human cadaveric islets, and the need for high doses of immunosuppressants due to immune rejection complications. Immunosuppression is another therapeutic option that could be effective in early disease stages before significant β-cell mass is depleted due to the autoimmune nature of the disease. Within this frame of reference, immunomodulatory therapeutic approaches could be great for preserving β-cells from death before T1D manifestation, or in the recently-onset of T1D patients with a greater amount of functional β-cell mass. Retention of endogenous insulin secretion by β cells is an attractive goal for better glycemic control without severe hypo- or hyperglycemia episodes, and decreases the risk of microvascular complications. This treatment strategy could significantly delay disease onset and progression. As inflammation and autoimmune attack at the pancreas decrease, the β-cell mass starts to slowly regenerate and restore normal levels of insulin secretion.

1 How can MSCs help?

Therapy with mesenchymal stem cells (MSCs) is a feasible option to ameliorate T1D because of their systemic immunomodulatory and regenerative properties. MSCs could play an important role in immunomodulation in areas of inflammation by downregulation of proinflammatory cytokines, inhibiting maturation of DC, reducing CD8+ T-lymphocyte proliferation, and stimulation of the production of regulatory T cells that are depleted in T1D patients. hImage created with BioRender

Moreover, they could promote angiogenesis and regeneration processes through the secretion of various growth factors, such as basic fibroblast growth factor and vascular endothelial growth factors (VEGF), cytokines, and extracellular vesicles. Studies on animal diabetic models treated with MSCs have shown a significant reduction in hyperglycemia, which was evaluated by a decrease in serum glucose, an increase in insulin, and C-peptide levels. Additionally, MSCs treatment lowered the serum levels of both liver and kidney function markers in diabetic rats, demonstrating possible hepato-renal protective benefits of MSCs therapy in T1D patients. In addition, it was shown that MSCs have been beneficial in treating chronic complications of T1D, such as neuropathy, DN, retinopathy, and insufficient wound healing.

Currently, there are several clinical trials where the safety and efficacy of MSCs therapy for T1D patients are studied. Below are some of them along with links for further information on the study.

1. The prospective clinical study of MSCs intervention strategy was performed on twenty adult patients with recent-onset T1D. Patients were randomized to MSC treatment or to the control group. Residual β-cell function was estimated by C-peptide concentrations in blood in response to a mixed-meal tolerance test (MMTT) at 1-year follow-up. The patients in the control arm showed loss in both C-peptide peak values and C-peptide area under the curve (total amount of C-peptide) during the 1st year. In contrast, patients treated by MSCs have preserved or even increased these C-peptide values. No side effects of MSCs therapy were observed. It was concluded that autologous MSCs treatment in new-onset T1D could be a safe and promising strategy to slow disease progression and preserve β-cell function.

Read the full study here: https://diabetesjournals.org/diabetes/article/64/2 or/587/34045/Preserved-Cell- Function-in-Type-1-Diabetes-by

2. Another clinical trial was performed on 12 patients with newly-onset T1D (less than 3 months) to evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) transplantation. Six cases were treated by hUCMSCs transplantation and insulin, and the other six were treated by insulin alone. Patients were followed up for 9 months. Fasting blood glucose, HbA1c, and C-peptide levels were significantly normalized in the MSCs treated group compared with the control group. Control group has significantly reduced C peptide levels during the follow up period, but the other indexes remained unchanged. Thus, results showed that MSCs therapy has positive effects on the treatment of newly-onset T1D.

Read the full study here: https://www.cjter.com//EN/Y2011/V15/I23/4363

3.The long-term effects of the implantation of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) were investigated for 29 patients with newly onset T1DM. The patients were randomly divided into two groups, one was treated with WJ-MSCs and the other was treated with normal saline based on insulin intensive therapy. Patients were followed-up after the WJ- MSCs transplantation every month for the first 3 months and every 3 months for the next 21 months. There were no acute or chronic side effects in the group treated by WJ-MSCs. Both the HbA1c and C peptide values have significantly improved in patients treated by WJ-MSCs compared with the other group during the follow-up period. Thus, therapy with WJ-MSCs might restore the function of islet β cells in a longer time and is expected to be an effective strategy for the treatment of T1D.

Read the full study here: https://www.jstage.jst.go.jp/article/endocrj/60/3/60_EJ12-0343/_article

4. A nonrandomized, open-label, parallel-armed prospective study of UC-MSCs therapy for 53 patients aged 8 to 55 years was performed (ChiCTR2100045434). MSC-treated group (27 patients) received an initial systemic administration of allogeneic UC-MSCs, followed by a repeat infusion at 3 months, whereas the control group (26 patients) received standard care based on intensive insulin therapy. At the end of the 1st year follow-up, 11 recipients (11/27, 40.7%) in the MSC-treated group maintained clinical remission with over 10% increase from the baseline level in either fasting or postprandial C-peptide, whereas the control group had a significantly lower rate of clinical remission (3/26, 11.5%, p = 0.041). Moreover, two patients from MSC-treated adults achieved insulin independence within 3 months after the 1st transplantation and started insulin again 1 year and 20 months later. One MCS-treated recipient achieved an insulin-free state 6 months after the 2nd transplantation, and started insulin again 3.8 months later. No severe side effects from therapy were observed during this clinical trial.

Read the full study here: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02417-3? elqTrackId=de6116f2f1364d52b4a39346449c186f

5. Randomized triple-blinded, placebo-controlled phase I/II clinical trial assessed the safety and efficacy of transplanting autologous bone marrow-derived MSCs for treatment of 21 newly diagnosed T1D patients (aged from 8 to 40) (NCT04078308). The patients were diagnosed with T1D according to the diagnostic criteria and the ADA guidelines within six weeks before enrollment to this trial, and were already under classic insulin therapy. Each patient in the experimental group received two doses of MSCs and was followed for at least 1 year after transplantation. The results of this trial have shown that MSCs transplantation is safe and significantly reduces the number of hypoglycemic episodes. Early after T1D diagnosis, MSCs treatment combined with physical exercise have normalized HbA1c level, improved C-peptide level, shifted measured serum cytokine levels from pro-inflammatory patterns to anti- inflammatory, increased the number of regulatory T-cells in the peripheral blood, and improved the quality of life. Thus, autologous BM-MSCs transplantation appeared to be a safe and promising treatment in newly diagnosed T1D children suffering from hypoglycemic episodes.

Read the full study here: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-022-02941-w

6. A pilot randomized controlled open-label clinical study of umbilical cord UC- MSCs with autologous bone marrow mononuclear cell (aBM-MNC) stem cell transplantation was performed on 42 patients with established T1D to investigate the safety and impact on insulin secretion (NCT01374854). The treatment was safe and well tolerated. In the 1st year, metabolic measures improved in patients treated with stem cells. C-peptide area under the curve (AUC(C-Pep)) increased up to 105.7% in 20 of 21 responders, whereas it decreased near 7.7% in the control group; and insulin area under the curve increased 49.3%, whereas it decreased 5.7% in the control group. HbA1c decreased from 12.6% to 7.5 ± 1.0% in the treated group, whereas it increased about 1.2% in the control group. Fasting glycemia decreased to 24.4% and 4.3% in control subjects. Daily insulin requirements decreased to 29.2% only in the treated group with no change found in control subjects. Thus, transplantation of UC-MSC and aBM-MNC appeared safe and resulted in glucose metabolism improvement in patients with established T1D.

Read the full study here: https://diabetesjournals.org/care/article/39/1/149/31805/Umbilical-Cord-Mesenchymal- Stromal-Cell-With

7. Exploring the long-term safety and benefit of the trial NCT01374854, the authors report about the incidence of chronic diabetes complications along with safety, islet function, and metabolic control after 8 years of follow-up. Data were obtained from 14 out of 21 patients in the UC-MSCs with aBM- MNC stem cell transplantation (SCT) group, and 15 out of 21 patients in the control group who completed this follow-up. No malignancies were reported in the SCT group. For 8 years, the incidence of peripheral neuropathy was 7.1% (one out of 14 patients) in the SCT group versus 46.7% (seven out of 15 patients) in the control group (P = 0.017). The incidence of diabetic nephropathy was 7.1% (one out of 14) in the SCT group versus 40.0% (six out of 15) in the control group (P = 0.039). The incidence of retinopathy was 7.1% (one out of 14) in the SCT group versus 33.3% (five out of 15) in the control group (P = 0.081). Two patients (14.3%) in the SCT group and 11 patients (73.3%) in the control group developed at least one complication (P = 0.001). At least two complications were observed in 7.1% of patients in the STC group and in 40% of patients in the control group (P = 0.039). Thus, co-transplantation of umbilical cord MSCs and aBM-MNCs in patients with established T1D could reduce the incidence of chronic diabetes complications in the long-term period.

Read the full study here: https://www.isct-cytotherapy.org/article/S1465-3249(21)00825-2/fulltext

Overall, the onset of T1D manifestation reflects a critical loss of β cells mass over an extended period of time along with impaired functioning of the immune system. However, the autoimmune destruction of insulin- secreting pancreatic β cells could be detected prior to the symptoms occurring by specific antibody tests.

Kintaro Cells offers safe and effective therapy with bone marrow-derived mesenchymal stem cells (BM-MSCs) for cases of newly diagnosed T1D. However, we believe that therapy with Kintaro Cells will be more effective when the smaller number of beta cells has already been destroyed. Therefore, the prophylactic administration of Kintaro Cells as an immunomodulatory therapy for genetically predisposed persons with “multiple positive antibodies” blood test results could delay the onset of T1D. Perhaps, it can even prevent its onset since the β cells mass is capable of slow regeneration, which will be promoted by MSCs secreted growth factors. For patients with established T1D disease, Kintaro Cells treatment might be effective to alleviate chronic T1D complications.


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