Shu Weigang, Wang Yongheng, Chen Mengfan, Zhu Xiaoli, Wang Fangtao, Chen Chunqiu, Du Peng, Bartolomucci Alexandra, Su Xin, Wang Xiaolei
Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of General Surgery, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Clin Transl Med. 2024 Dec;14(12):e70086. doi: 10.1002/ctm2.70086.
Crohn's disease (CD) is a chronic inflammatory disease in the intestinal tract. Mesenteric fat wrapping and thickening, or creeping fat (CrF), is a typical characteristic of CD and it involves lymphangiogenesis and altered lymphatic function. By releasing extracellular vesicles (EVs), adipose tissue-derived stem cells (ADSCs) can regulate their adjacent cells. However, the regulating roles of ADSC-EVs in CrF (CrF-EVs) in CD, especially in modulating lymphatic function and mitigating the progression of mesenteritis and colitis, remains elusive.
To evaluate the regulative roles of CrF-EVs on lymphatic functions, in vitro assays were performed using human lymphatic endothelial cells (HLECs). Next, Interleukin 10 knock-out (Il-10) mice were used to assess the biological functions of CrF-EVs in spontaneous mesenteritis and colitis. Moreover, tissue and serum from various cohorts of CD patients were used to determine the prognostic value of miR-132-3p.
CrF-EVs significantly attenuated spontaneous mesenteritis and colitis in Il-10 mice via promoting lymphangiogenesis and lymphatic drainage. Using high-throughput sequencing, we demonstrated that CrF-EVs significantly increased HLEC proliferation, migration, tube formation and CCL-21 production in a miR-132-3p/RASA1/ERK1/2 axis-dependent manner. Accordingly, upregulated miR-132-3p was observed in patient CrF, positively correlated with lymphangiogenesis while negatively correlated with inflammatory factors (tumour necrosis factor-α and IL-6) level. Moreover, serum miR-132-3p demonstrated a positive correlation with disease activity.
EVs derived from CrF ADSCs, containing elevated levels of miR-132-3p, could promote lymphatic function and restrain inflammation of CD. Our results provide a novel insight into the role of mesenteric lymphatics in CD progression and reveal a new potential therapeutic.
Extracellular vesicles (EVs) of creeping fat (CrF) derived adipose stem cells effectively attenuate chronic mesenteritis and colitis in Crohn's disease (CD). The lymphatic vessels play an important role in disease development of CD and their functions are improved by CrF-EV-miR-132-3p through RASA1/ERK1/2 signaling. MiR-132-3p expression is upregulated in CrF and serum of CD patients, and tightly linked with inflammation and disease activity.
克罗恩病（CD）是一种肠道慢性炎症性疾病。肠系膜脂肪包裹和增厚，即爬行脂肪（CrF），是CD的典型特征，它涉及淋巴管生成和淋巴功能改变。脂肪组织来源的干细胞（ADSCs）通过释放细胞外囊泡（EVs）可以调节其相邻细胞。然而，ADSC-EVs在CD的CrF（CrF-EVs）中的调节作用，尤其是在调节淋巴功能和减轻小肠炎和结肠炎进展方面，仍不清楚。
为了评估CrF-EVs对淋巴功能的调节作用，使用人淋巴管内皮细胞（HLECs）进行了体外试验。接下来，使用白细胞介素10基因敲除（Il-10）小鼠评估CrF-EVs在自发性小肠炎和结肠炎中的生物学功能。此外，使用来自不同队列的CD患者的组织和血清来确定miR-132-3p的预后价值。
CrF-EVs通过促进淋巴管生成和淋巴引流，显著减轻了Il-10小鼠的自发性小肠炎和结肠炎。通过高通量测序，我们证明CrF-EVs以miR-132-3p/RASA1/ERK1/2轴依赖性方式显著增加HLEC增殖、迁移、管腔形成和CCL-21产生。因此，在患者的CrF中观察到miR-132-3p上调，与淋巴管生成呈正相关，而与炎症因子（肿瘤坏死因子-α和IL-6）水平呈负相关。此外，血清miR-132-3p与疾病活动呈正相关。
源自CrF ADSCs的EVs，其miR-132-3p水平升高，可促进淋巴功能并抑制CD的炎症。我们的结果为肠系膜淋巴管在CD进展中的作用提供了新的见解，并揭示了一种新的潜在治疗方法。
爬行脂肪（CrF）来源的脂肪干细胞的细胞外囊泡（EVs）有效减轻克罗恩病（CD）中的慢性小肠炎和结肠炎。淋巴管在CD的疾病发展中起重要作用，并且CrF-EV-miR-132-3p通过RASA1/ERK1/2信号传导改善其功能。miR-132-3p在CD患者的CrF和血清中表达上调，并且与炎症和疾病活动密切相关。
