Nonmyeloablative Stem Cell Therapy Enhances Microcirculation and Tissue Regeneration in Murine Inflammatory Bowel Disease

Background & Aims: Reduced microcirculation has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Stem cells or endothelial progenitor cells are thought to contribute to tissue regeneration through neoangiogenesis or vasculogenesis in ischemia- or inflammatory-related diseases. We therefore hypothesized that adult stem cells facilitate epithelial repair in IBD. Methods: Moderate–severe colitis in mice was induced by dextran sulfate sodium (DSS) and 2.0 × 10⁶ immortalized CD34⁻ stem cells infused twice via the tail vein during an observation period of 35 days in a nonmyeloablative setting. Results: Here, we demonstrate that adult stem cells home to the damaged digestive tract in the large intestine and facilitate mucosal repair in moderate-severe colitis. Nonmyeloablative stem cell therapy resulted in increased survival in severe colitis (P < .0001). Moreover, clinical activity and histologic evaluation of the colitis severity score were reduced significantly in moderate (P = .0003 or P = .03) and severe (P < .0001 or P < .03) colitis after 35 days, in addition to the DSS-induced shortening of colon length (P = .002 and P < .0002). Genetically marked stem cells were detected predominately in the submucosa of the damaged colon epithelium. Epithelial repair in experimental IBD was mediated either by induction of improved vasculogenesis or by the differentiation of the transplanted stem cells into endothelial cells, as demonstrated by the promotion of Tie2 activity in the infused cells at the site of the damaged mucosa. Conclusions: Our findings indicate that systemically administered adult stem cells respond to an adequate tissue lesion in murine IBD by enhancing microcirculation, resulting in accelerated tissue repair.

Abbreviations used in this paper: CAS, clinical activity score, DAPI, 4’,6’-diamidino-2-phenylindole, DSS, dextran sulfate sodium, Flt-1, FMS-like tyrosine kinase 1 or vascular endothelial growth factor receptor (VEGF-R1), GFP, green fluorescence protein, H&E, hematoxylin & eosin, MSC, mesenchymal stem cells, MW, molecular weight, PECAM-1, platelet-endothelial cell adhesion molecule (CD31 antigen), RFP, red fluorescence protein, SC, stem cells, SCL, stem cell leukemia or stem-cell leukemia hematopoietic transcription factor (tal1), SV40, simian virus 40, Tie2, endothelium-specific receptor tyrosine kinase 2