Cell Therapy for Hirschsprung Disease-Associated Enterocolitis: Evaluation of the Effects and Safety of Mesenchymal Stem Cells on Intestinal Macrophages

MSCs have significant immune regulation ability. In this study, we applied MSCs to the treatment of HAEC, a common life threatening complication of HSCR. We aimed to investigate the effectiveness and long-term safety of MSCs based therapy for HAEC and the underlying mechanisms through in vivo and in vitro experiments. In our study, HSCR and HAEC samples were used to assess the inflammation 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. We found that intestinal M1 macrophage activation and severe inflammation condition were observed in HAEC. After the injection of MSCs, HAEC mice showed significant amelioration of the inflammatory injury and predominance of M2 macrophages rather than M1 macrophages. Besides, the expression levels of pro-inflammatory cytokines were decreased and anti-inflammatory cytokines were increased. In addition, we found that effective MSCs homing to the inflamed colon tissue occurred without long-term toxicity response. However, a COX2 inhibitor could diminish the therapeutic effects of MSCs on HAEC. Using MSCs and macrophages coculture system, we identified that MSCs could alleviate HAEC through COX2 dependent MAPK ERK signaling pathway by promoting M1 to M2 polarization. In conclusion, MSCs could ameliorate HAEC symptoms by promoting M1 to M2 phenotype polarization via COX2 mediated MAPK ERK signaling pathway, thus providing novel insights and potentially promising strategy for the treatment or prevention of HAEC.