Local administration of stem cell-derived extracellular vesicles in a thermoresponsive hydrogel promotes a pro-healing effect in a rat model of colo-cutaneous post-surgical fistula

Berger, A; Araújo‐Filho, Irami; Piffoux, Max; Nicolas‐Boluda, Alba; Grangier, Alice; Boucenna, Imane; Real, Caroline Cristiano; Marques, Fábio Luiz Navarro; Faria, Daniele de Paula; Rêgo, Amália Cínthia Meneses; Broudin, Chloé; Gazeau, Florence; Wilhelm, Claire; Clémеnt, Olivier; Cellier, Christophe; Buchpiguel, Carlos Alberto; Rahmi, Gabriel; Silva, Amanda

doi:10.1039/d0nr07349k

Cited by 27 publications

(29 citation statements)

References 66 publications

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“…The only exception being the category of liver diseases in the cases of which the natural hepatic docking of EVs eliminates the necessity of specific EV targeting. As a solution, local administration of EVs has been suggested in different studies [51][52][53]. A deeper understanding of the EV scavenger processes by individual liver cell populations may enable the development of therapeutic approaches with blocking or targeting different liver cell populations.…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicle release and uptake by the liver under normo- and hyperlipidemia

Németh

Varga

Lenzinger

et al. 2021

Cell. Mol. Life Sci.

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Liver plays a central role in elimination of circulating extracellular vesicles (EVs), and it also significantly contributes to EV release. However, the involvement of the different liver cell populations remains unknown. Here, we investigated EV uptake and release both in normolipemia and hyperlipidemia. C57BL/6 mice were kept on high fat diet for 20–30 weeks before circulating EV profiles were determined. In addition, control mice were intravenously injected with 99mTc-HYNIC-Duramycin labeled EVs, and an hour later, biodistribution was analyzed by SPECT/CT. In vitro, isolated liver cell types were tested for EV release and uptake with/without prior fatty acid treatment. We detected an elevated circulating EV number after the high fat diet. To clarify the differential involvement of liver cell types, we carried out in vitro experiments. We found an increased release of EVs by primary hepatocytes at concentrations of fatty acids comparable to what is characteristic for hyperlipidemia. When investigating EV biodistribution with 99mTc-labeled EVs, we detected EV accumulation primarily in the liver upon intravenous injection of mice with medium (326.3 ± 19.8 nm) and small EVs (130.5 ± 5.8 nm). In vitro, we found that medium and small EVs were preferentially taken up by Kupffer cells, and liver sinusoidal endothelial cells, respectively. Finally, we demonstrated that in hyperlipidemia, there was a decreased EV uptake both by Kupffer cells and liver sinusoidal endothelial cells. Our data suggest that hyperlipidema increases the release and reduces the uptake of EVs by liver cells. We also provide evidence for a size-dependent differential EV uptake by the different cell types of the liver. The EV radiolabeling protocol using 99mTc-Duramycin may provide a fast and simple labeling approach for SPECT/CT imaging of EVs biodistribution.

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Section: Discussionmentioning

confidence: 99%

Extracellular vesicle release and uptake by the liver under normo- and hyperlipidemia

Németh

Varga

Lenzinger

et al. 2021

Cell. Mol. Life Sci.

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“…One of the major contributions of our study is that we investigated the proposed nano-therapy in a porcine model, allowing us to ascertain esophageal stricture disease, administration modalities as well as the required therapeutic doses relevant to humans in a translational approach. Another strength of our study is the association of nanoscale EVs with a thermoresponsive biomaterial constituted of nano-micelles 36,38 to prevent esophageal strictures. Our results strengthen the view that a combination of EVs and a biomaterial may improve the biomaterial therapeutic effect while facilitating EV administration.…”

Section: Discussionmentioning

confidence: 99%

“…This thermoresponsive gel composed of nano-micelles is expected to allow minimally invasive injection in the liquid state at <20°C and gelation in situ at body temperature to favor EV residence time in the site of interest. 36 Besides being a delivery vehicle, PF-127 seems to be beneficial for wound healing by recruiting some factors like VEGF and TGFβ1 and increasing the density of micro-vessels, collagen level and rate of formation of granulation tissue. 37 Our team previously evidenced the therapeutic effect of ADSC EVs and PF-127 gel for esophageal fistula healing in a porcine model.…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles from adipose stromal cells combined with a thermoresponsive hydrogel prevent esophageal stricture after extensive endoscopic submucosal dissection in a porcine model

et al. 2021

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“…Particularly, mesenchymal stem cell-derived EV therapies are quickly moving toward clinical applications [ 131 ]. Stem cell-based EV therapies have been evaluated in the context of post-surgical wound healing, specifically for the treatment of colo-cutaneuous fistulas and ischemia–reperfusion injury [ 132 , 133 ]. Furthermore, pharmacological inhibition of EV biogenesis (i.e.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Extracellular vesicles: mediators of intercellular communication in tissue injury and disease

et al. 2021

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Intercellular communication is a critical process that ensures cooperation between distinct cell types and maintains homeostasis. EVs, which were initially described as cellular debris and devoid of biological function, are now recognized as key components in cell–cell communication. EVs are known to carry multiple factors derived from their cell of origin, including cytokines and chemokines, active enzymes, metabolites, nucleic acids, and surface molecules, that can alter the behavior of recipient cells. Since the cargo of EVs reflects their parental cells, EVs from damaged and dysfunctional tissue environments offer an abundance of information toward elucidating the molecular mechanisms of various diseases and pathological conditions. In this review, we discuss the most recent findings regarding the role of EVs in the progression of cancer, metabolic disorders, and inflammatory lung diseases given the high prevalence of these conditions worldwide and the important role that intercellular communication between immune, parenchymal, and stromal cells plays in the development of these pathological states. We also consider the clinical applications of EVs, including the possibilities for their use as novel therapeutics.

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Local administration of stem cell-derived extracellular vesicles in a thermoresponsive hydrogel promotes a pro-healing effect in a rat model of colo-cutaneous post-surgical fistula

Abstract: Local minimally-invasive EV delivery on a thermo-actuated PF-127 gel enhanced EV residence time in colo-cutaneous fistulas promoting a therapeutic effect.

Cited by 27 publications

References 66 publications

Extracellular vesicle release and uptake by the liver under normo- and hyperlipidemia

Extracellular vesicle release and uptake by the liver under normo- and hyperlipidemia

Extracellular vesicles from adipose stromal cells combined with a thermoresponsive hydrogel prevent esophageal stricture after extensive endoscopic submucosal dissection in a porcine model

Extracellular vesicles: mediators of intercellular communication in tissue injury and disease

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