Transplantation of MHC-mismatched mouse embryonic stem cell-derived thymic epithelial progenitors and MHC-matched bone marrow prevents autoimmune diabetes
Transplantation of MHC-mismatched mouse embryonic stem cell-derived thymic epithelial progenitors and MHC-matched bone marrow prevents autoimmune diabetes
复制标题
移植 MHC 不匹配的小鼠胚胎干细胞来源的胸腺上皮祖细胞和 MHC 匹配的骨髓可预防自身免疫性糖尿病。
DOI：
10.1186/s13287-019-1347-1
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发表时间：
2019-08-06
影响因子：
7.5
通讯作者：
Lai, Laijun
中科院分区：
文献类型：
--
作者：
Su, Min;Lin, Yujun;Lai, Laijun
1型糖尿病（T1D）是一种自身免疫性疾病，由自身反应性T细胞破坏分泌胰岛素的胰岛β细胞引起。非肥胖糖尿病小鼠（NOD）是目前广泛应用的人类T1D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）位点和胰岛自身抗原在胸腺中的表达和/或呈递受损有关，从而导致中枢和外周耐受缺陷。据报道，与mhc不匹配的供体骨髓（BM）移植诱导混合嵌合，而不是mhc不匹配的供体骨髓（BM）移植，可阻止NOD小鼠发生T1D。我们已经报道了小鼠胚胎干细胞（mESCs）可以在体外选择性诱导产生胸腺上皮祖细胞（TEPs）， TEPs在体内进一步发育为胸腺上皮细胞（TECs），以支持T细胞的发育。方法为确定mhc错配的mESC-TEPs移植是否能预防胰岛素炎和T1D的发生，对NOD小鼠进行条件化并注射mhc错配的B6 mESC-TEPs和mhc -匹配的H-2(g7) B6小鼠BM。监测小鼠的T1D发育情况。然后从小鼠身上采集胰腺、脾脏、BM和胸腺，以评估T1D、胰岛素、嵌合水平和T细胞。结果mhc不匹配的mESC-TEPs和mhc匹配的供体BM移植可预防NOD小鼠的胰岛素和T1D的发生。这与mesc - tec中关键的胰岛自身抗原胰岛素原2的高表达和调节性T细胞数量的增加有关。结论胚胎干细胞衍生的TEPs可能为控制T1D提供了一种新的途径。
Background Type 1 diabetes (T1D) is an autoimmune disease resulting from the destruction of insulin-secreting islet beta 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. Methods 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(g7) 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. Results 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. Conclusions Our results suggest that embryonic stem cell-derived TEPs may offer a new approach to control T1D.