Pharmacological Mobilization and Recruitment of Stem Cells in Rats Stops Abdominal Adhesions After Laparotomy

Kenichi Iwasaki,Melissa Chen,Wei Wang,Le Qi,Kenji Katsumata,Zhaoli Sun,Andrew M Cameron,James Burdick,Ali Reza Ahmadi,Akihiko Tsuchida

doi:10.1038/s41598-019-43734-1

Kenichi Iwasaki, Melissa Chen + Show 8 more

Open Access

https://doi.org/10.1038/s41598-019-43734-1

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Abstract

Adhesions are a very common complication in the abdominal surgery. Animal studies and human trials have evaluated strategies designed to reduce and prevent postsurgical adhesions but few have an evidence base that justifies routine use. A strategy to prevent adhesions effectively remains an urgent need. We studied a reproducible model of intra-peritoneal adhesion formation in rats using laparotomy with several peritoneal sutures to produce the adhesions. Here we show that entraining endogenous stem cells into injury sites using the combined effect of AMD3100 and low-dose FK-506 (AF) can reduce the adhesion score significantly and abolish peritoneal adhesions in 45% of animals in a rat model of severe postsurgical intra-abdominal adhesions, compared with saline controls. 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. Our results demonstrate that medically induced recruitment of autologous stem cells using AF significantly reduced postsurgical intra-abdominal adhesions. These findings suggest a novel effective therapeutic approach to preventing adhesions in patients.

Highlights

Animals that received a combination of AMD3100 and FK506 (AF) therapy sc displayed significantly less intra-abdominal adhesion formation (Fig. 2A): about 45% animals (5/11) showed few intra-abdominal adhesions, 18% animals with mild intra-abdominal adhesions (2/11), 18% (2/11) animals developed moderate intra-abdominal adhesions and only 18% animals had severe intra-abdominal adhesions (Fig. 2B)
We have reported a synergy between AMD3100 and low-dose FK506 for entrainment of bone marrow-derived CD133 stem cells into damaged tissue[12,13,14,15,16]
Production of hepatocyte growth factor (HGF) by infiltrating M2 macrophages may promote healing of the injured peritoneal surface and contribute to freedom from peritoneal scarring. These findings show the importance of endogenous bone marrow-derived stem cells in preventing postsurgical adhesions

Summary

Introduction

In experiments with 85% partial hepatectomy it was noted that adhesions were minimized in the test group receiving combination therapy[16] Based on these observations, we hypothesized that medical conscription and recruitment of undifferentiated bone marrow cells by this drug combination may promote regeneration of damaged peritoneal surfaces following surgery, and prevents the formation of peritoneal adhesions. We hypothesized that medical conscription and recruitment of undifferentiated bone marrow cells by this drug combination may promote regeneration of damaged peritoneal surfaces following surgery, and prevents the formation of peritoneal adhesions We test this hypothesis objectively by testing it in severe peritoneal scarring in rats. We show that this treatment was able to reduce the adhesion score significantly and abolish peritoneal adhesions in 45% of animals

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Conclusion