Annexin A1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair
Giovanna Leoni, … , Andrew S. Neish, Asma Nusrat
Giovanna Leoni, … , Andrew S. Neish, Asma Nusrat
Published February 9, 2015
Citation Information: J Clin Invest. 2015;125(3):1215-1227. https://doi.org/10.1172/JCI76693.
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Research Article Gastroenterology

Annexin A1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair

Abstract

Epithelial restitution is an essential process that is required to repair barrier function at mucosal surfaces following injury. Prolonged breaches in epithelial barrier function result in inflammation and further damage; therefore, a better understanding of the epithelial restitution process has potential for improving the development of therapeutics. In this work, we demonstrate that endogenous annexin A1 (ANXA1) is released as a component of extracellular vesicles (EVs) derived from intestinal epithelial cells, and these ANXA1-containing EVs activate wound repair circuits. Compared with healthy controls, patients with active inflammatory bowel disease had elevated levels of secreted ANXA1-containing EVs in sera, indicating that ANXA1-containing EVs are systemically distributed in response to the inflammatory process and could potentially serve as a biomarker of intestinal mucosal inflammation. Local intestinal delivery of an exogenous ANXA1 mimetic peptide (Ac2-26) encapsulated within targeted polymeric nanoparticles (Ac2-26 Col IV NPs) accelerated healing of murine colonic wounds after biopsy-induced injury. Moreover, one-time systemic administration of Ac2-26 Col IV NPs accelerated recovery following experimentally induced colitis. Together, our results suggest that local delivery of proresolving peptides encapsulated within nanoparticles may represent a potential therapeutic strategy for clinical situations characterized by chronic mucosal injury, such as is seen in patients with IBD.

Authors

Giovanna Leoni, Philipp-Alexander Neumann, Nazila Kamaly, Miguel Quiros, Hikaru Nishio, Hefin R. Jones, Ronen Sumagin, Roland S. Hilgarth, Ashfaqul Alam, Gabrielle Fredman, Ioannis Argyris, Emile Rijcken, Dennis Kusters, Chris Reutelingsperger, Mauro Perretti, Charles A. Parkos, Omid C. Farokhzad, Andrew S. Neish, Asma Nusrat

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Figure 6

Intramucosal injections of Ac2-26 Col IV NPs augment colonic mucosal wound healing.

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Intramucosal injections of Ac2-26 Col IV NPs augment colonic mucosal wou...
(A) Images obtained during colonoscopy showing intramucosal injection of NPs in the mucosal wound bed. The arrow delineates the area of submucosal injection. (B) Schematic showing intramucosal NP injection into the colonic mucosal wounds. (C) Frozen sections of resealing colonic wounds in Anxa1+/+ mice showing ANXA1 (red), F-actin (Alexa Fluor 488 phalloidin, green), and NPs (Alexa Fluor 647, blue). Higher-magnification images (original magnification, ×40) of the boxed region (original magnification, ×20) are shown to the right. Scale bar: 50 μm. (D) Frozen sections labeled for F-actin (Alexa Fluor 555 phalloidin, red). Released Ac2-26-FAM is shown in green and labeled Ac2-26 Col IV NPs are shown in blue. A higher-magnification image of the boxed region is shown to the right. Scale bar: 50 μm. (E) Immunoblot analysis of ANXA1 expression in nonwounded and resealing wounds of Anxa1+/+ mice. Equivalent amounts of protein were loaded. From densitometry analysis ANXA1 protein in wounded tissue is increased versus nonwounded cells (2.568-fold increase, P = 0.0005, average of n = 3 immunoblots). (F) Endoscopic images of healing colonic mucosal wounds 1 or 3 days after biopsy-induced injury in Anxa1–/– mice treated with NPs. (G) Quantification of wound repair. Data are expressed as mean ± SEM; n = 15 mice per group. ***P < 0.0001 vs. Scrm Ac2-26 Col IV NPs and vs. Ac2-26. Statistical comparisons were performed by ANOVA with Tukey’s multiple comparison post-test.