Nonmyeloablative stem cell therapy enhances microcirculation and tissue regeneration in murine inflammatory bowel disease.
OBJECTIVE
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 x 10(6) 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 predominantly 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.
Khalil
Philipe N
PN
Department of Surgery, Klinikum Innenstadt, Ludwig-Maximilians-Universität of München, Munich, Germany. philipe.khalil@med.uni-muenchen.de
Weiler
Véronique
V
Nelson
Peter J
PJ
Khalil
Maurice N
MN
Moosmann
Sabine
S
Mutschler
Wolf E
WE
Siebeck
Matthias
M
Huss
Ralf
R
D000208:Acute Disease; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D003106:Colon / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D007413:Intestinal Mucosa / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008833:Microcirculation; D018919:Neovascularization, Physiologic; D042787:Receptor, TIE-2 / Q000378:metabolism; D012038:Regeneration; D012720:Severity of Illness Index; D033581:Stem Cell Transplantation / Q000379:methods; D013997:Time Factors
D016264:Dextran Sulfate; D042787:Receptor, TIE-2