Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin- induced diabetes
- Resource Type
- Authors
- Siyang Liu; Bin Zhang; Yanting Wen; Jingjing Ding; Ningning Zong; Shiyun Zhang; Hongwei Wang; Yixue Zhang; Dongyue Chen; Ying Wang; Qianqian Dai; Qian Gao
- Source
- Ann Transl Med
- Subject
- medicine.medical_specialty
endocrine system diseases
business.industry
hemic and immune systems
chemical and pharmacologic phenomena
General Medicine
Syngeneic Bone Marrow Transplantation
medicine.disease
Streptozotocin
Endocrinology
immune system diseases
Diabetes mellitus
Internal medicine
medicine
Original Article
Stage (cooking)
business
PI3K/AKT/mTOR pathway
medicine.drug
- Language
- ISSN
- 2305-5847
2305-5839
BACKGROUND: Type 1 diabetes (T1D) is a multiple factor autoimmune disease characterized by T cell-mediated immune destruction of islet β cells. Autologous hematopoietic stem cell transplantation (AHSCT) has been a novel strategy for patients with new-onset T1D, but not for those with a later diagnosis. Disturbance of regulatory T cells (Tregs) likely contributes to poor response after transplantation in later-stage T1D. Inhibition of phosphoinositide 3-kinases (PI3K)/Akt signaling maintains Tregs’ homeostasis. METHODS: We built a later-stage streptozotocin (STZ)-induced T1D mouse model. Syngeneic bone marrow transplantation (syn-BMT) was performed 20 days after the onset of diabetes in combination with BKM120 (a PI3K inhibitor). Meanwhile, another group of STZ-diabetic mice were transplanted with bone marrow cells cocultured with BKM120 in vitro for 24 h. Fasting glucose and glucose tolerance were recorded during the entire experimental observation after syn-BMT. Samples were collected 126 days after syn-BMT. Hematoxylin and eosin (H&E) staining was used to detect the effect of PI3K inhibitor combined with syn-BMT on morphology of the T1D pancreas. CD4(+)CD25(−) T cells and CD4(+)CD25(+) T cells were sorted by magnetic cell sorting (MACS), then fluorescence activated cell sorting (FACS) and quantitative real-time PCR (qPCR) were used to detect the effect of PI3K inhibitor on modulating immune disorder and restoring the function of Treg cells. RESULTS: Our investigation showed syn-BMT in combination with BKM120 effectively maintained normoglycemia in later-stage T1D. The disease remission effects may be induced by the rebalance of Th17/Tregs dysregulation and restoration of Tregs’ immunosuppressive function by BKM120 after syn-BMT. CONCLUSIONS: These results may reveal important connections for PI3K/Akt inhibition and Tregs’ homeostasis in T1D after transplantation. AHSCT combining immunoregulatory strategies such as PI3K inhibition may be a promising therapeutic approach in later-stage T1D.