Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.

Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of...

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Autores principales:	Katelyn J McCann, Manoj Yadav, Mohammadali E Alishahedani, Alexandra F Freeman, Ian A Myles
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3c6f3139923447a4858c9425239074d7
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spelling	oai:doaj.org-article:3c6f3139923447a4858c9425239074d72021-12-02T20:04:09ZDifferential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.1932-620310.1371/journal.pone.0248011https://doaj.org/article/3c6f3139923447a4858c9425239074d72021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0248011https://doaj.org/toc/1932-6203Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.Katelyn J McCannManoj YadavMohammadali E AlishahedaniAlexandra F FreemanIan A MylesPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 3, p e0248011 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katelyn J McCann Manoj Yadav Mohammadali E Alishahedani Alexandra F Freeman Ian A Myles Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
description	Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism-a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.
format	article
author	Katelyn J McCann Manoj Yadav Mohammadali E Alishahedani Alexandra F Freeman Ian A Myles
author_facet	Katelyn J McCann Manoj Yadav Mohammadali E Alishahedani Alexandra F Freeman Ian A Myles
author_sort	Katelyn J McCann
title	Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
title_short	Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
title_full	Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
title_fullStr	Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
title_full_unstemmed	Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.
title_sort	differential responses to folic acid in an established keloid fibroblast cell line are mediated by jak1/2 and stat3.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/3c6f3139923447a4858c9425239074d7
work_keys_str_mv	AT katelynjmccann differentialresponsestofolicacidinanestablishedkeloidfibroblastcelllinearemediatedbyjak12andstat3 AT manojyadav differentialresponsestofolicacidinanestablishedkeloidfibroblastcelllinearemediatedbyjak12andstat3 AT mohammadaliealishahedani differentialresponsestofolicacidinanestablishedkeloidfibroblastcelllinearemediatedbyjak12andstat3 AT alexandraffreeman differentialresponsestofolicacidinanestablishedkeloidfibroblastcelllinearemediatedbyjak12andstat3 AT ianamyles differentialresponsestofolicacidinanestablishedkeloidfibroblastcelllinearemediatedbyjak12andstat3
_version_	1718375595679678464

Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3.

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