Pharmacological Mobilization and Recruitment of Endogenous Stem Cells Prevents Postsurgical Intra-Abdominal Adhesion in Rats

Abstract

Background: Postsurgical adhesions are a very common complication causing various symptoms from pain to bowel obstruction. We have developed a stem cell mobilizing strategy that enables long-term liver and kidney allograft survival without sustained immunosuppression in animals using a combination of AMD3100 and low-dose FK506 (AF). Serendipitously we have noted a subjective decrease in adhesion formation in animals with AF combination treatment. The purpose of this study was to evaluate the effect of a new stem cell mobilizing strategy on preventing postsurgical adhesion formation in rats. Methods: Abdominal adhesions were induced by creating suture knots on the parietal peritoneum in Lewis rats. Animals were divided randomly into four experimental groups and received subcutaneous injections of saline, single drug or AF combination every other day for 10 days. On postoperative day 14, animals were euthanized and the severity of adhesions were evaluated and scored blindly by five individual surgeons. Results: Most animals treated with saline or single drug exhibited severe peritoneal adhesions around sites of suture knots. AF combination significantly reduced the formation of peritoneal adhesions, 64% animals (7/11) showed few or mild adhesion and no animal showed severe peritoneal adhesions. Searching for mechanisms, we found AF treatment dramatically increased SDF-1 expressing cells, HGF expressing Ym1 M2 macrophages and CD133 stem cells in the injury sites of peritoneal surface at day 5 post-operation. Conclusion: Pharmacological mobilization and recruitment of endogenous stem cells using AF combination significantly reduced postsurgical intra-abdominal adhesions in rats. These findings suggest a novel therapeutic approach to preventing postsurgical adhesions in patients undergoing abdominal or pelvic surgery. Funding Statement: This work was supported by a start-up fund from the surgical department at Johns Hopkins University. Declaration of Interests: None of the authors has a financial interest in any of the products, or drugs mentioned in this manuscript. Ethics Approval Statement: Animals were maintained in a pathogen-free facility of Johns Hopkins University School of Medicine and all animal experiments were performed in accordance with the United States National Institutes of Health (NIH) guidance. All animal protocols were reviewed and approved by the Johns Hopkins University Animal Care and Use Committee.