Meng Xinyao, Xiao Jun, Wang Jing, Sun Minxian, Chen Xuyong, Wu Luyao, Chen Ke, Li Zejian, Feng ChenZhao, Zhuansun Didi, Yang Jixin, Wu Xiaojuan, Yu Donghai, Li Wei, Niu Yonghua, He Ying, Wei Mingfa, Chen Feng, Xiong Bo, Feng Jiexiong, Zhu Tianqi
Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Center of Hirschsprung Disease and Allied Disorders, Wuhan, China.
Department of Endocrinology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
J Pediatr Surg. 2024 Aug;59(8):1498-1514. doi: 10.1016/j.jpedsurg.2024.02.033. Epub 2024 Mar 4.
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 in vivo and in vitro.
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.
先天性巨结肠相关小肠结肠炎（HAEC）是先天性巨结肠（HSCR）常见的危及生命的并发症。我们旨在研究基于间充质干细胞（MSCs）的疗法对HAEC的有效性、长期安全性及潜在机制。
使用HSCR和HAEC患者的标本评估炎症状况。将内皮素受体B（Ednrb）基因敲除小鼠用作HAEC模型。将MSCs腹腔注射到HAEC小鼠体内。在体内和体外探索MSCs治疗HAEC的疗效、长期结果、安全性和毒性以及机制。
在HAEC中观察到肠道M1巨噬细胞浸润和严重炎症状况。注射MSCs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）的表达水平升高。此外，我们发现有效的MSCs归巢至炎症结肠组织，且无长期毒性反应。然而，COX-2抑制剂可减弱MSCs的治疗效果。利用MSCs与巨噬细胞共培养系统，我们确定MSCs可通过COX-2依赖性MAPK/ERK信号通路抑制M1巨噬细胞活化，从而减轻HAEC。
MSCs通过COX-2介导的MAPK/ERK信号通路减少M1巨噬细胞极化，从而改善HAEC，为HAEC的治疗或预防提供了新的见解和潜在的有前景的策略。
