Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. KEY POINTS: 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.