Potentials of bone marrow cells-derived from naïve or diabetic mice in autoimmune type 1 diabetes: immunomodulatory, anti-inflammatory, anti hyperglycemic, and antioxidative
Authors: Gomaa Soha , Nassef Mohamed , Hafez Amira 
Published: July 2024

Abstract
Background:
The scarcity of transplanted human islet tissue and the requirement for immunosuppressive drugs to prevent the rejection of allogeneic grafts have hindered the treatment of autoimmune type 1 diabetes mellitus (T1DM) through islet transplantation. However, there is hope in adoptively transferred bone marrow cells (BMCs) therapy, which has emerged as a propitious pathway for forthcoming medications. BMCs have the potential to significantly impact both replacement and regenerative therapies for a range of disorders, including diabetes mellitus, and have demonstrated anti-diabetic effects.

Aim:
The main goal of this study is to evaluate the effectiveness of adoptively transferred bone marrow cells derived from either naïve mice (nBMCs) or diabetic mice (dBMCs) in treating a T1DM mice model.

Methods:
Male Swiss albino mice were starved for 16 h and then injected with streptozotocin (STZ) at a dose of 40 mg/kg body weight for 5 consecutive days to induce T1DM. After 14 days, the diabetic mice were distributed into four groups. The first group served as a diabetic control treated with sodium citrate buffer, while the other three groups were treated for two weeks, respectively, with insulin (subcutaneously at a dose of 8 U/kg/day), nBMCs (intravenously at a dose of 1 × 106 cells/mouse/once), and dBMCs (intravenously at a dose of 1 × 106 cells/mouse/once).

Results:
It is worth noting that administering adoptively transferred nBMCs or adoptively transferred dBMCs to STZ-induced T1DM mice resulted in a significant amelioration in glycemic condition, accompanied by a considerable reduction in the level of blood glucose and glycosylated hemoglobin % (HbA1C %), ultimately restoring serum insulin levels to their initial state in control mice. Administering nBMCs or dBMCs to STZ-induced T1DM mice led to a remarkable decrease in levels of inflammatory cytokine markers in the serum, including interferon-γ (INF-γ), tumor necrosis factor- α (TNF-α), tumor growth factor-β (TGF-β), interleukin-1 β (L-1β), interlekin-4 (IL-4), interleukin-6 (IL-6), and interleukin-10 (IL-10). Additionally, STZ-induced T1DM mice, when treated with nBMCs or dBMCs, experienced a notable rise in total immunoglobulin (Ig) level. Furthermore, there was a significant reduction in the levels of islet cell autoantibodies (ICA) and insulin autoantibodies (IAA). Furthermore, the serum of STZ-induced T1DM mice showed a significant increase in Zinc transporter 8 antigen protein (ZnT8), islet antigen 2 protein (IA-2), and glutamic acid decarboxylase antigen protein (GAD) levels. Interestingly, the administration of nBMCs or dBMCs resulted in a heightened expression of IA-2 protein in STZ-induced T1DM mice treated with nBMCs or dBMCs. Furthermore, the level of malondialdehyde (MDA) was increased, while the levels of catalase (CAT) and superoxide dismutase (SOD) were decreased in non-treated STZ-induced T1DM mice. However, when nBMCs or dBMCs were administered to STZ-induced T1DM mice, it had a significant impact on reducing oxidative stress. This was accomplished by reducing the levels of MDA in the serum and enhancing the activities of enzymatic antioxidants like CAT and SOD. STZ-induced T1DM mice displayed a significant elevation in the levels of liver enzymes ALT and AST, as well as heightened levels of creatinine and urea. Considering the crucial roles of the liver and kidney in metabolism and excretion, this research further examined the effects of administering nBMCs or dBMCs to STZ-induced T1DM mice. Notably, the administration of these cells alleviated the observed effects.

Conclusion:
The present study suggests that utilizing adoptively transferred nBMCs or adoptively transferred dBMCs in the treatment of T1DM led to noteworthy decreases in blood glucose levels, possibly attributed to their capacity to enhance insulin secretion and improve the performance of pancreatic islets. Additionally, BMCs may exert their beneficial effects on the pancreatic islets of diabetic mice through their immunomodulatory, antioxidant, anti-inflammatory, and anti-oxidative stress properties.