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Int. J. Mol. Sci. 2017, 18(9), 1915; doi:10.3390/ijms18091915

The Role of Focal Adhesion Kinase in Keratinocyte Fibrogenic Gene Expression

1
Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305-5148, USA
2
Program in Biomedical Informatics, Stanford University School of Medicine, Stanford, CA 94305-5148, USA
*
Author to whom correspondence should be addressed.
Received: 28 June 2017 / Revised: 31 August 2017 / Accepted: 1 September 2017 / Published: 7 September 2017
(This article belongs to the Special Issue Recent Advances in Scar Biology)
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Abstract

Abnormal skin scarring causes functional impairment, psychological stress, and high socioeconomic cost. Evidence shows that altered mechanotransduction pathways have been linked to both inflammation and fibrosis, and that focal adhesion kinase (FAK) is a key mediator of these processes. We investigated the importance of keratinocyte FAK at the single cell level in key fibrogenic pathways critical for scar formation. Keratinocytes were isolated from wildtype and keratinocyte-specific FAK-deleted mice, cultured, and sorted into single cells. Keratinocytes were evaluated using a microfluidic-based platform for high-resolution transcriptional analysis. Partitive clustering, gene enrichment analysis, and network modeling were applied to characterize the significance of FAK on regulating keratinocyte subpopulations and fibrogenic pathways important for scar formation. Considerable transcriptional heterogeneity was observed within the keratinocyte populations. FAK-deleted keratinocytes demonstrated increased expression of genes integral to mechanotransduction and extracellular matrix production, including Igtbl, Mmpla, and Col4a1. Transcriptional activities upon FAK deletion were not identical across all single keratinocytes, resulting in higher frequency of a minor subpopulation characterized by a matrix-remodeling profile compared to wildtype keratinocyte population. The importance of keratinocyte FAK signaling gene expression was revealed. A minor subpopulation of keratinocytes characterized by a matrix-modulating profile may be a keratinocyte subset important for mechanotransduction and scar formation. View Full-Text
Keywords: focal adhesion kinase; keratinocyte; mechanotransduction; extracellular matrix; single-cell transcriptional analysis; skin fibrosis; hypertrophic scar; transcriptomics focal adhesion kinase; keratinocyte; mechanotransduction; extracellular matrix; single-cell transcriptional analysis; skin fibrosis; hypertrophic scar; transcriptomics
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Januszyk, M.; Kwon, S.H.; Wong, V.W.; Padmanabhan, J.; Maan, Z.N.; Whittam, A.J.; Major, M.R.; Gurtner, G.C. The Role of Focal Adhesion Kinase in Keratinocyte Fibrogenic Gene Expression. Int. J. Mol. Sci. 2017, 18, 1915.

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