Small IntestineProtective effect of adipose tissue–derived mesenchymal stromal cells in an experimental model of high-risk colonic anastomosis
Introduction
Among the postoperative complications in colorectal operations, anastomotic dehiscence represents a serious problem to the patient because of its potential consequences, such as fecal peritonitis and sepsis.1 It has been estimated that about one third of deaths related to anastomotic dehiscence can be attributed to the extravasation of colorectal contents after operative procedures.2 The morbidity associated with anastomotic dehiscence results in increased durations of hospital stay, costs, and mortality, and a greater risk of cancer recurrence.3, 4, 5
The incidence of anastomotic dehiscence with leakage has been related to several variables, such as the operative procedure (elective or emergency), the topography (right or left large bowel and upper or lower rectum), the presence of intestinal obstruction, and local factors such as intestinal microbiota, shear forces resulting from peristalsis, fecal transit, and underlying diseases.2 In particular, in the presence of inflammatory bowel disease (IBD), dehiscence of an intestinal anastomosis represents a severe, post-operative complication with greater morbidity and mortality. Moreover, it has been estimated that more than half of the patients with Crohn’s disease (CD) will require an operative procedure within 10 years after diagnosis.6, 7 Currently, notwithstanding all accumulated knowledge in the field of IBD, available therapies are still of limited efficacy and continue to impose important safety concerns. In view of the need for safer and more effective options, cell-based therapies have been investigated as potential novel alternatives.8, 9
Mesenchymal stromal cells (MSCs) constitute a subset of nonhematopoietic stem cells with multi-lineage potential that can be found in various tissues, including bone marrow, skin, muscle, and fat.10 In fat tissues, these cells are referred to as adipose tissue-derived mesenchymal stromal cells (AT-MSCs) and represent an abundant source of functional cells, potentially relevant to therapeutic applications using autologous or allogeneic MSCs.11 The interest in using MSCs for treating chronic inflammatory diseases is because they are home to inflammatory sites where they promote immunomodulatory effects and participate in tissue repair.12, 13 In human IBD, AT-MSCs have been used recently with relatively successful results. For example, complete healing of fistulas was observed in >80% of patients with CD in a modified, intention-to-treat analysis in which AT-MSCs were injected directly into fistula tracts, with no adverse events.14 In a phase 3, randomized, double-blind controlled trial in patients with CD with perianal fistula, a single intralesional injection of expanded allogeneic AT-MSCs resulted in more effective closure with less treatment-related adverse events than the placebo group.15 In experimental models of anastomosis, performed either on ischemic colon16 or after high-dose irradiation,17 treatment with MSCs promoted accelerated healing. In this study, our aim was to evaluate the potential beneficial effect of locally administered AT-MSCs in a rodent model of a high-risk colonic anastomosis.
Section snippets
Ethics statement
All procedures reported in this study were in compliance with Brazilian national regulations for animal experiments and were in accordance with the guidelines of the International Care and Use Committee of the National Institutes of Health, and Guide for the Care and Use of Laboratory Animals.18 The institutional animal care committee of the Federal University of Rio de Janeiro approved the care and use of animals and the procedures carried out in this study (approval number # 004/15).
Animals and experimental groups
The study
Treatment with AT-MSCs decreased postanastomotic morbidity and mortality
During the follow-up period after the operative procedure, no changes in weight were detected among the animals regardless of the treatment. Macroscopic analysis of the abdominal cavity, however, showed greater colonic distension, wall thickening, and more exuberant perianastomotic adhesions in groups 1 and 5 (submitted to TNBS-induced colitis). Local complications, including fistula, abscess, and peritonitis, were observed in 8 animals submitted to the high-risk anastomosis and treated with
Discussion
In this study, the beneficial effects of the topical application of AT-MSCs were demonstrated in a high-risk colonic anastomosis in a rat model of colitis. Regarding efficacy, AT-MSCs prevented the mortality and complications associated with this high-risk colonic anastomosis, and consistently stabilized the intestinal architecture after 1 week of treatment. In particular, we demonstrated that topical application of AT-MSCs contributed to the preservation of epithelial integrity, stabilizing
Funding/Support
This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (302401/2016-4) and the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (E26/202.781/2017).
Conflict of interest/Disclosure
The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
Acknowledgments
We thank Jose Nazioberto D. de Farias and Alyson do Rosario Jr. for their technical assistance with the tissue processing.
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2022, Surgery (United States)Citation Excerpt :The authors also found that when using quantitative RT-PCR, SC-treated animals had a 5.9-fold and 7.4-fold increase in the expression of vascular endothelial growth factors at days 3 and 7. In a different model where a high-risk anastomosis was constructed by inducing chemical colitis before creation of the anastomosis, Alvarenga et al35 studied rats that were treated with 2X106 adipose tissue–derived mesenchymal SCs. In comparison to the control groups where acellular culture solution was installed, the SC-treated animals showed no postoperative complications as compared to a 53% postoperative complication rate (fistula, abscess, and peritonitis) in the nontreated group.
Effects of adipose tissue-derived mesenchymal stem cells and/or sildenafil citrate in experimental colon anastomosis model
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Medical student from the Federal University of Rio de Janeiro.