Department of Child HealthCare, Affiliated Foshan Maternity & Child Healthcare Hospital, The Second School of Clinical Medicine of Southern Medical University, Foshan, P. R. China.
Department of Child Psychiatry, Kangning Hospital of Shenzhen, Shenzhen Mental Health Center, Shenzhen, P. R. China.
Ann N Y Acad Sci. 2022 Jun;1512(1):98-113. doi: 10.1111/nyas.14766. Epub 2022 Feb 27.
Epidemiological studies have shown that maternal diabetes is associated with autism spectrum disorder development, although the detailed mechanism remains unclear. We have previously found that maternal diabetes induces persistent epigenetic changes and gene suppression in neurons, subsequently triggering autism-like behavior (ALB). In this study, we investigated the potential role and effect of hematopoietic stem cells (HSCs) on maternal diabetes-mediated gastrointestinal (GI) dysfunction and ALB in a mouse model. We show in vitro that transient hyperglycemia induced persistent epigenetic changes and gene suppression of tight junction proteins. In vivo, maternal diabetes-mediated oxidative stress induced gene suppression and inflammation in both peripheral blood mononuclear cells and intestine epithelial cells, subsequently triggering GI dysfunction with increased intestinal permeability and altered microbiota compositions, as well as suppressed gene expression in neurons and subsequent ALB in offspring; HSC transplantation (HSCT) ameliorates this effect by systematically reversing maternal diabetes-mediated oxidative stress. We conclude that HSCT can ameliorate maternal diabetes-mediated GI symptoms and autism-like behavior in mouse offspring.
流行病学研究表明，母体糖尿病与自闭症谱系障碍的发展有关，尽管其详细机制尚不清楚。我们之前发现，母体糖尿病会在神经元中诱导持续的表观遗传变化和基因抑制，从而引发类似自闭症的行为（ALB）。在这项研究中，我们在小鼠模型中研究了造血干细胞（HSCs）对母体糖尿病介导的胃肠道（GI）功能障碍和 ALB 的潜在作用和影响。我们在体外表明，短暂的高血糖会引起紧密连接蛋白的持续表观遗传变化和基因抑制。在体内，母体糖尿病介导的氧化应激会诱导外周血单个核细胞和肠上皮细胞中的基因抑制和炎症，随后导致肠道通透性增加和微生物群落组成改变，以及神经元中的基因表达受抑制，随后出现后代的 ALB；造血干细胞移植（HSCT）通过系统地逆转母体糖尿病介导的氧化应激来改善这种作用。我们得出结论，HSCT 可以改善母体糖尿病介导的小鼠后代的胃肠道症状和自闭症样行为。
