Hirschsprung disease-associated enterocolitis (HAEC) is a common life-threatening complication of Hirschsprung disease (HSCR). We aimed to investigate the effectiveness, long-term safety and the underlying mechanisms of Mesenchymal stem cells (MSCs) based therapy for HAEC. Specimens from HSCR and HAEC patients were used to assess the inflammatory condition. Ednrb knock-out mice was used as HAEC model. MSCs was intraperitoneally transplanted into HAEC mice. The therapy effects, long-term outcome, safety and toxicity and the mechanism of MSCs on the treatment of HAEC were explored and Intestinal M1 macrophages infiltration and severe inflammation condition were observed in HAEC. After the injection of MSCs, HAEC mice showed significant amelioration of the inflammatory injury and inhibition of M1 macrophages infiltration. The expression levels of pro-inflammatory cytokines (TNF-α and IFN-γ) were decreased and anti-inflammatory cytokines (IL-10 and TGF-β) were increased. In addition, we found that effective MSCs homing to the inflamed colon tissue occurred without long-term toxicity response. However, COX-2 inhibitor could diminish the therapeutic effects of MSCs. Using MSCs and macrophages co-culture system, we identified that MSCs could alleviate HAEC by inhibiting M1 macrophages activation through COX-2-dependent MAPK/ERK signaling pathway. MSCs ameliorate HAEC by reducing M1 macrophages polarization via COX-2 mediated MAPK/ERK signaling pathway, thus providing novel insights and potentially promising strategy for the treatment or prevention of HAEC.

中文翻译：

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间充质干细胞通过 COX-2 依赖性机制减少 M1 巨噬细胞浸润，减轻先天性巨结肠疾病 - 相关小肠结肠炎

先天性巨结肠症相关小肠结肠炎 (HAEC) 是先天性巨结肠症 (HSCR) 常见的危及生命的并发症。我们的目的是研究基于间充质干细胞 (MSC) 的 HAEC 治疗的有效性、长期安全性和潜在机制。来自 HSCR 和 HAEC 患者的标本用于评估炎症状况。使用Ednrb基因敲除小鼠作为HAEC模型。 MSCs被腹膜内移植到HAEC小鼠体内。探讨间充质干细胞治疗HAEC的疗效、远期疗效、安全性和毒性以及机制，并观察HAEC中肠道M1巨噬细胞浸润和严重炎症情况。注射MSC后，HAEC小鼠的炎症损伤明显改善，M1巨噬细胞浸润受到抑制。促炎细胞因子（TNF-α和IFN-γ）的表达水平降低，抗炎细胞因子（IL-10和TGF-β）的表达水平增加。此外，我们发现有效的间充质干细胞归巢到发炎的结肠组织，而没有长期毒性反应。然而，COX-2抑制剂可能会降低MSC的治疗效果。使用 MSC 和巨噬细胞共培养系统，我们发现 MSC 可以通过 COX-2 依赖性 MAPK/ERK 信号通路抑制 M1 巨噬细胞活化来缓解 HAEC。 MSC 通过 COX-2 介导的 MAPK/ERK 信号通路减少 M1 巨噬细胞极化来改善 HAEC，从而为治疗或预防 HAEC 提供新的见解和潜在有前途的策略。