Molecular mechanisms of esophageal epithelial regeneration following repair of surgical defects with acellular silk fibroin grafts

Abstract

Constructive remodeling of focal esophageal defects with biodegradable acellular grafts relies on the ability of host progenitor cell populations to repopulate implant regions and facilitate growth of de novo functional tissue. Intrinsic molecular mechanisms governing esophageal repair processes following biomaterial-based, surgical reconstruction is largely unknown. In the present study, we utilized mass spectrometry-based quantitative proteomics and in silico pathway evaluations to identify signaling cascades which were significantly activated during neoepithelial formation in a Sprague Dawley rat model of onlay esophagoplasty with acellular silk fibroin scaffolds. Pharmacologic inhibitor and rescue experiments revealed that epithelialization of neotissues is significantly dependent in part on pro-survival stimuli capable of suppressing caspase activity in epithelial progenitors via activation of hepatocyte growth factor receptor (c-MET), tropomyosin receptor kinase A (TrkA), phosphoinositide 3-kinase (PI3K), and protein kinase B (Akt) signaling mechanisms. These data highlight the molecular machinery involved in esophageal epithelial regeneration following surgical repair with acellular implants.

Silk Fibroin/Hydroxyapatite Coating Improved Osseointegration of Porous Titanium Implants under Diabetic Conditions via Activation of the PI3K/Akt Signaling Pathway

“…The critical role of PI3K/Akt signaling in SF or HA’s regulation of cellular biological functions has also been illustrated before. Gundogdu et al in their recent study demonstrated that PI3K/Akt signaling was a significant regulator in the repair process of surgical defects of esophageal epithelial tissue with SF grafts . Gemini-Piperni et al suggested that HA triggered Akt and other intracellular signaling pathways in the early process of osteoblast adhesion, which activated proteins involving cytoskeleton rearrangement, as well as induction of osteoblastic differentiation .…”

“…Gundogdu et al in their recent study demonstrated that PI3K/Akt signaling was a significant regulator in the repair process of surgical defects of esophageal epithelial tissue with SF grafts. 46 Gemini-Piperni et al suggested that HA triggered Akt and other intracellular signaling pathways in the early process of osteoblast adhesion, which activated proteins involving cytoskeleton rearrangement, as well as induction of osteoblastic differentiation. 27 In the current study, we found that the SF/HA hybrid coating significantly reactivated the DM-suppressed PI3K/Akt pathway, which exhibited the same effect as the ROS scavenger NAC.…”

DNA Methylation Dynamics During Esophageal Epithelial Regeneration Following Repair with Acellular Silk Fibroin Grafts in Rat

“…The average log 2 fold protein expression of DEPs which were previously identified in postsurgical timepoints compared to the NSC for biological replicates (4 for each condition). The proteomics data were obtained from Gundogdu et al [8] B) Left: Scatterplot displaying the methylation difference for NSC→Day1 DMCs that fall within gene bodies, as well as the log 2 fold protein expression value for the protein encoded by the gene associated with that DMC. Orange line represents linear regression and gray shading represents 95% confidence interval.…”

“…[6] Bilayer silk fibroin (BLSF) scaffolds represent an emerging platform for esophageal repair due to their high structural strength and elasticity, low immunogenicity, and tunable degradative properties, [7] These matrices have been previously demonstrated to support the formation of innervated, vascularized esophageal tissues with contractile properties sufficient for solid food ingestion in preclinical animal models. [7,8] Constructive remodeling of BLSF scaffolds is dependent on the ability of host progenitor cell populations to migrate, proliferate, and differentiate within the implant microenvironment to facilitate regeneration of functional neotissues. [7] Molecular mechanisms governing scaffold-mediated wound healing processes in the esophagus are largely unexplored.…”

Regenerative medicine for childhood gastrointestinal diseases

“…Evidence from lineage tracing and cell cycle tracing data in mice suggest oesophageal epithelial homeostasis is supported by a single stem population of progenitor cells stochastically producing one daughter for stem maintenance and one for subsequent differentiation [20]. When injury occurs, cells close to the wound transiently increase the production of progenitor cells, allowing for rapid replacement of the superficial layer as part of a co-ordinated set of responses involving molecular signals including, EGF, HGF/c-MET and NGF/TrkA [21,22].…”