Abstract：
Patients with inflammatory bowel disease (IBD) have a higher risk of developing colitis-associated colorectal cancer (CAC) with poor prognosis. IBD etiology remains undefined but involves environmental factors, genetic predisposition, microbiota imbalance (dysbiosis) and mucosal immune defects. Mesenchymal stromal cell (MSC) injections have shown good efficacy in reducing intestinal inflammation in animal and human studies. However, their effect on tumor growth in CAC and their capacity to restore gut dysbiosis are not clear.
The outcome of systemic administrations of in vitro expanded human intestinal MSCs (iMSCs) on tumor growth in vivo was evaluated using the AOM/DSS model of CAC in C57BL/6J mice. Innate and adaptive immune responses in blood, mesenteric lymph nodes (MLNs) and colonic tissue were analyzed by flow cytometry. Intestinal microbiota composition was evaluated by 16S rRNA amplicon sequencing.
iMSCs significantly inhibited colitis and intestinal tumor development, reducing IL-6 and COX-2 expression, and IL-6/STAT3 and PI3K/Akt signaling. iMSCs decreased colonic immune cell infiltration, and partly restored intestinal monocyte homing and differentiation. iMSC administration increased the numbers of Tregs and IFN-γ+CD8+ T cells in the MLNs while decreasing the IL-4+Th2 response. It also ameliorated intestinal dysbiosis in CAC mice, increasing diversity and Bacillota/Bacteroidota ratio, as well as Akkermansia abundance, while reducing Alistipes and Turicibacter, genera associated with inflammation.
Administration of iMSCs protects against CAC, ameliorating colitis and partially reverting intestinal dysbiosis, supporting the use of MSCs for the treatment of IBD.
The outcome of systemic administrations of in vitro expanded human intestinal MSCs (iMSCs) on tumor growth in vivo was evaluated using the AOM/DSS model of CAC in C57BL/6J mice. Innate and adaptive immune responses in blood, mesenteric lymph nodes (MLNs) and colonic tissue were analyzed by flow cytometry. Intestinal microbiota composition was evaluated by 16S rRNA amplicon sequencing.
iMSCs significantly inhibited colitis and intestinal tumor development, reducing IL-6 and COX-2 expression, and IL-6/STAT3 and PI3K/Akt signaling. iMSCs decreased colonic immune cell infiltration, and partly restored intestinal monocyte homing and differentiation. iMSC administration increased the numbers of Tregs and IFN-γ+CD8+ T cells in the MLNs while decreasing the IL-4+Th2 response. It also ameliorated intestinal dysbiosis in CAC mice, increasing diversity and Bacillota/Bacteroidota ratio, as well as Akkermansia abundance, while reducing Alistipes and Turicibacter, genera associated with inflammation.
Administration of iMSCs protects against CAC, ameliorating colitis and partially reverting intestinal dysbiosis, supporting the use of MSCs for the treatment of IBD.
摘要：
背景：炎症性肠病（IBD）患者发生结肠炎相关性结直肠癌（CAC）的风险较高，预后较差。IBD病因尚不明确，但涉及环境因素，遗传易感性,微生物群失衡（菌群失调）和粘膜免疫缺陷。在动物和人类研究中，间充质基质细胞（MSC）注射在减轻肠道炎症方面显示出良好的功效。然而,它们对CAC中肿瘤生长的影响及其恢复肠道生态失调的能力尚不清楚。
方法:使用CAC的AOM/DSS模型在C57BL/6J小鼠中评估体外扩增的人肠MSCs(iMSCs)的全身施用对体内肿瘤生长的结果。血液中的固有和适应性免疫反应，通过流式细胞术分析肠系膜淋巴结（MLN）和结肠组织。通过16SrRNA扩增子测序评估肠道微生物群组成。
结果：iMSCs显著抑制结肠炎和肠道肿瘤的发展，降低IL-6和COX-2表达，以及IL-6/STAT3和PI3K/Akt信号传导。iMSCs减少结肠免疫细胞浸润，部分恢复肠单核细胞归巢和分化。iMSC施用增加MLN中Treg和IFN-γ+CD8+T细胞的数量,同时降低IL-4+Th2应答。它还改善了CAC小鼠的肠道生态失调，增加多样性和芽孢杆菌/拟杆菌比例，以及Akkermansia的丰富，同时减少Alistipes和Turicibacter，与炎症相关的属。
结论：给予iMSCs可保护CAC，改善结肠炎和部分恢复肠道生态失调，支持使用MSCs治疗IBD。
方法:使用CAC的AOM/DSS模型在C57BL/6J小鼠中评估体外扩增的人肠MSCs(iMSCs)的全身施用对体内肿瘤生长的结果。血液中的固有和适应性免疫反应，通过流式细胞术分析肠系膜淋巴结（MLN）和结肠组织。通过16SrRNA扩增子测序评估肠道微生物群组成。
结果：iMSCs显著抑制结肠炎和肠道肿瘤的发展，降低IL-6和COX-2表达，以及IL-6/STAT3和PI3K/Akt信号传导。iMSCs减少结肠免疫细胞浸润，部分恢复肠单核细胞归巢和分化。iMSC施用增加MLN中Treg和IFN-γ+CD8+T细胞的数量,同时降低IL-4+Th2应答。它还改善了CAC小鼠的肠道生态失调，增加多样性和芽孢杆菌/拟杆菌比例，以及Akkermansia的丰富，同时减少Alistipes和Turicibacter，与炎症相关的属。
结论：给予iMSCs可保护CAC，改善结肠炎和部分恢复肠道生态失调，支持使用MSCs治疗IBD。
