Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin-induced diabetes

Shiyun Zhang; Qianqian Dai; Bin Zhang; Siyang Liu; Ying Wang; Yixue Zhang; Dongyue Chen; Ningning Zong; Hongwei Wang; Jingjing Ding; Qian Gao; Yanting Wen

doi:10.21037/atm-21-3329

Syngeneic bone marrow transplantation in combination with PI3K inhibitor reversed hyperglycemia in later-stage streptozotocin-induced diabetes

Ann Transl Med. 2021 Nov;9(22):1642. doi: 10.21037/atm-21-3329.

Authors

Shiyun Zhang^#¹, Qianqian Dai^#¹, Bin Zhang^#¹, Siyang Liu¹, Ying Wang¹, Yixue Zhang¹, Dongyue Chen¹, Ningning Zong¹, Hongwei Wang¹, Jingjing Ding², Qian Gao¹, Yanting Wen¹

Affiliations

¹ Department of Basic Medicine, Center of Translational Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University Medical School, Nanjing, China.
² Department of Respiratory Medicine, Jiangsu Key Laboratory of Molecular Medicine, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

^# Contributed equally.

Abstract

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.

Keywords: BKM120; Type 1 diabetes (T1D); phosphoinositide 3-kinases (PI3K)/Akt signaling; regulatory T cells (Tregs); syngeneic bone marrow transplantation (syn-BMT).