Berger Arthur, Araújo-Filho Irami, Piffoux Max, Nicolás-Boluda Alba, Grangier Alice, Boucenna Imane, Real Caroline Cristiano, Marques Fabio Luiz Navarro, de Paula Faria Daniele, do Rego Amália Cinthia Meneses, Broudin Chloe, Gazeau Florence, Wilhelm Claire, Clément Olivier, Cellier Christophe, Buchpiguel Carlos Alberto, Rahmi Gabriel, Silva Amanda K A
Laboratoire Imagerie de l'Angiogénèse, Plateforme d'Imagerie du Petit Animal, PARCC, INSERM U970, Université de Paris, 75015, Paris, France.
Nanoscale. 2021 Jan 7;13(1):218-232. doi: 10.1039/d0nr07349k. Epub 2020 Dec 16.
Extracellular vesicles (EVs), especially from stem/stromal cells (SCs), represent a cell-free alternative in regenerative medicine holding promises to promote tissue healing while providing safety and logistic advantages in comparison to cellular counterparts. Herein, we hypothesize that SC EVs, administered locally in a thermoresponsive gel, is a therapeutic strategy for managing post-surgical colo-cutaneous fistulas. This disease is a neglected and challenging condition associated to low remission rates and high refractoriness. Herein, EVs from a murine SC line were produced by a high-yield scalable method in bioreactors. The post-surgical intestinal fistula model was induced via a surgical cecostomy communicating the cecum and the skin in Wistar rats. Animals were treated just after cecostomy with PBS, thermoresponsive Pluronic F-127 hydrogel alone or containing SC EVs. A PET-monitored biodistribution investigation of SC EVs labelled with Zr was performed. Fistula external orifice and output assessment, probe-based confocal laser endomicroscopy, MRI and histology were carried out for therapy follow-up. The relevance of percutaneous EV administration embedded in the hydrogel vehicle was indicated by the PET-biodistribution study. Local administration of SC EVs in the hydrogel reduced colo-cutaneous fistula diameter, output, fibrosis and inflammation while increasing the density of neo-vessels when compared to the PBS and gel groups. This multi-modal investigation pointed-out the therapeutic potential of SC EVs administered locally and in a thermoresponsive hydrogel for the management of challenging post-surgical colon fistulas in a minimally-invasive cell-free strategy.
细胞外囊泡（EVs），尤其是来自干/基质细胞（SCs）的细胞外囊泡，在再生医学中代表了一种无细胞替代方案，有望促进组织愈合，同时与细胞对应物相比具有安全性和后勤优势。在此，我们假设局部注射到热敏凝胶中的SCs EVs是一种治疗手术后结肠皮肤瘘的策略。这种疾病是一种被忽视且具有挑战性的病症，缓解率低且难治性高。在此，通过生物反应器中的高产可扩展方法产生了来自小鼠SC系的EVs。通过手术盲肠造口术在Wistar大鼠中诱导建立手术后肠瘘模型，使盲肠与皮肤相通。动物在盲肠造口术后立即用PBS、单独的热敏性泊洛沙姆F - 127水凝胶或含有SCs EVs的水凝胶进行治疗。对用Zr标记的SCs EVs进行了PET监测的生物分布研究。进行瘘管外口和排出量评估、基于探针的共聚焦激光内镜检查、MRI和组织学检查以进行治疗随访。PET生物分布研究表明了嵌入水凝胶载体中的经皮EV给药的相关性。与PBS和凝胶组相比，在水凝胶中局部施用SCs EVs可减小结肠皮肤瘘的直径、减少排出量、减轻纤维化和炎症，同时增加新血管密度。这项多模态研究指出了以微创无细胞策略局部施用并置于热敏水凝胶中的SCs EVs在治疗具有挑战性的手术后结肠瘘方面的治疗潜力。
