Macrophage Phenotype Is Associated With the Regenerative Response in Experimental Replacement of the Porcine Esophagus

Abstract

A porcine model for bridging circumferential defects in the intrathoracic esophagus has been developed in order to improve the treatment of children born with long-gap esophageal atresia. The aim of this study was to identify factors beneficial for tissue regeneration in the bridging area in this model and to describe the histological progression 20 days after replacement with a silicone-stented Biodesign mesh. Resection of 3 cm of intrathoracic esophagus and replacement with a bridging graft was performed in six newly weaned piglets. They were fed through a gastrostomy for 10 days, and then had probe formula orally for another 10 days prior to sacrifice. Two out of six piglets had stent loss prior to sacrifice. In the four piglets with the stent in place, a tissue tube, with visible muscle in the wall, was seen at sacrifice. Histology showed that the wall of the healing area was well organized with layers of inflammatory cells, in-growing vessels, and smooth muscle cells. CD163+ macrophages was seen toward the esophageal lumen. In the animals where the stent was lost, the bridging area was narrow, and histology showed a less organized structure in the bridging area without the presence of CD163+ macrophages. This study indicates that regenerative healing was seen in the porcine esophagus 20 days after replacement of a part of the intrathoracic esophagus with a silicone-stented Biodesign mesh, if the bridging graft is retained. If the graft is lost, the inflammatory pattern changes with invasion of proinflammatory, M1 macrophages in the entire wall, which seems to redirect the healing process toward scar formation.

Long-term regeneration and remodeling of the pig esophagus after circumferential resection using a retrievable synthetic scaffold carrying autologous cells

“…These endogenous MSCs may be supplemented to facilitate healing for chronic wounds, and are able to be isolated from various mesenchymal tissues autologous from patients such as adipose, bone marrow, tendon, muscle, and skin 48 . While these cells themselves are unlikely to engraft into the tissue even if autologous, stimulation of angiogenesis 49 , neovascularization, and inhibition of fibrosis 50 – 52 would have significant benefits for esophageal healing and remodeling as inhibition of a fibrotic response is likely required for functional regrowth. Mesenchymal stem cells have the unique potential of acting on multiple regenerative pathways 48 – 52 .…”

“…While these cells themselves are unlikely to engraft into the tissue even if autologous, stimulation of angiogenesis 49 , neovascularization, and inhibition of fibrosis 50 – 52 would have significant benefits for esophageal healing and remodeling as inhibition of a fibrotic response is likely required for functional regrowth. Mesenchymal stem cells have the unique potential of acting on multiple regenerative pathways 48 – 52 . Healing requires a coordinated signaling and response between cells, extracellular matrix, and signaling factors.…”

Decellularization of porcine esophageal tissue at three diameters and the bioscaffold modification with EETs‐ECM gel

“…It was expected to ameliorate the proinflammatory response of macrophages in vitro based on the modulatory activity of lipid mediators in acute and chronic inflammation and fibrosis in wound healing 25,38 . The transition from a proinflammatory to an antiinflammatory phenotype of macrophages has been observed in the luminal side of a replaced porcine esophagus 39 . The dependence of macrophage cell line viability on EETs concentration reported in this work may be related to fact that these substances were initially dissolved in ethanol.…”

“…25,38 The transition from a proinflammatory to an antiinflammatory phenotype of macrophages has been observed in the luminal side of a replaced porcine esophagus. 39 The dependence of macrophage cell line viability on EETs concentration reported in this work may be related to fact that these substances were initially dissolved in ethanol. Although a number lower of iNOS-expressing cells were detected on EETs-ECM gel coated bioscaffolds, the results are inconclusive to show the bioactivity of those in modifying the response of this macrophage cell line.…”

A Scarless Healing Tale: Comparing Homeostasis and Wound Healing of Oral Mucosa With Skin and Oesophagus

“…The cellular and molecular mechanisms underlying oesophageal wound healing have recently attracted attention. Despite comparisons with gastric healing, the similarities to the epidermis have also prompted studies to disclose possible critical players in oesophageal response to wounding ( Baatar et al, 2002a , b ; Chai et al, 2007 ; Tarnawski and Ahluwalia, 2012 ; Jönsson et al, 2016 ; Tabola et al, 2016 ; Cai et al, 2018 ; Komaki et al, 2019 ; Boudaka et al, 2020 ).…”