Department of Human Histology and Embryology, School of Basic Medical Sciences, Stem Cell and Tissue Engineering Research Centre, Guizhou Medical University, Guiyang, Guizhou, China.
Department of Allied Health Sciences, University of Connecticut, 1390 Storrs Road, Storrs, CT, 06269, USA.
Stem Cell Res Ther. 2019 Aug 6;10(1):239. doi: 10.1186/s13287-019-1347-1.
Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-secreting islet β cells by autoreactive T cells. Non-obese diabetic (NOD) mice are the widely used animal model for human T1D. Autoimmunity in NOD mice is associated with particular major histocompatibility complex (MHC) loci and impaired islet autoantigen expression and/or presentation in the thymus, which results in defects in both central and peripheral tolerance. It has been reported that induction of mixed chimerism with MHC-mismatched, but not MHC-matched donor bone marrow (BM) transplants prevents the development T1D in NOD mice. We have reported that mouse embryonic stem cells (mESCs) can be selectively induced in vitro to generate thymic epithelial progenitors (TEPs) that further develop into thymic epithelial cells (TECs) in vivo to support T cell development.
To determine whether transplantation of MHC-mismatched mESC-TEPs could prevent the development of insulitis and T1D, NOD mice were conditioned and injected with MHC-mismatched B6 mESC-TEPs and MHC-matched BM from H-2 B6 mice. The mice were monitored for T1D development. The pancreas, spleen, BM, and thymus were then harvested from the mice for evaluation of T1D, insulitis, chimerism levels, and T cells.
Transplantation of MHC-mismatched mESC-TEPs and MHC-matched donor BM prevented insulitis and T1D development in NOD mice. This was associated with higher expression of proinsulin 2, a key islet autoantigen in the mESC-TECs, and an increased number of regulatory T cells.
Our results suggest that embryonic stem cell-derived TEPs may offer a new approach to control T1D.
1 型糖尿病（T1D）是一种自身免疫性疾病，由自身反应性 T 细胞破坏胰岛β细胞引起。非肥胖型糖尿病（NOD）小鼠是广泛用于研究人类 T1D 的动物模型。NOD 小鼠的自身免疫与特定的主要组织相容性复合体（MHC）位点有关，并且在胸腺中胰岛自身抗原的表达和/或呈递受损，导致中枢和外周耐受均存在缺陷。据报道，用 MHC 错配而非 MHC 匹配的供体骨髓（BM）移植诱导混合嵌合可预防 NOD 小鼠 T1D 的发生。我们已经报道，胚胎干细胞（mESCs）可以在体外被选择性地诱导生成胸腺上皮祖细胞（TEPs），这些细胞在体内进一步发育为胸腺上皮细胞（TECs），以支持 T 细胞发育。
为了确定 MHC 错配的 mESC-TEPs 移植是否可以预防胰岛炎和 T1D 的发生，我们对 NOD 小鼠进行了预处理并注射了 MHC 错配的 B6 mESC-TEPs 和 MHC 匹配的来自 H-2 B6 小鼠的 BM。监测这些小鼠 T1D 的发展情况。然后从这些小鼠中采集胰腺、脾脏、BM 和胸腺，以评估 T1D、胰岛炎、嵌合水平和 T 细胞。
移植 MHC 错配的 mESC-TEPs 和 MHC 匹配的供体 BM 可预防 NOD 小鼠的胰岛炎和 T1D 发展。这与关键胰岛自身抗原 proinsulin 2 的更高表达以及调节性 T 细胞数量的增加有关。
我们的结果表明，胚胎干细胞衍生的 TEPs 可能为控制 T1D 提供一种新方法。
