Inherent Features In Human Oral Epithelia Determine Heightened Wound Healing
Ramiro Iglesias-Bartolome1, Akihiko Uchiyama1, Rose Graf1, Alfredo A. Molinolo2, Loreto Abusleme3, Stephen R. Brooks4, Juan Luis Callejas-Valera2, Dean Edwards2, Colleen Doci2, Marie-Liesse Asselin-Labat5, Mark Onaitis5, Niki Moutsopoulos3, J. Silvio Gutkind2, Maria I. Morasso1.
1Laboratory of Skin Biology, NIAMS, NIH, Bethesda, MD, USA, 2Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, MD, USA, 3Oral Immunity and Inflammation Unit, NIDCR, NIH, Bethesda, MD, USA, 4Biodata Mining and Discovery Section, NIAMS, NIH., Bethesda, MD, USA, 5Moores Cancer Center, UCSD, La Jolla, CA, USA.
BACKGROUND - While oral wound healing has been considered an ideal system of wound resolution, the specific molecular events that differentiate oral wound healing are poorly understood in humans. METHODS - A human clinical study was performed to characterize the healing process and changes in gene expression between oral and cutaneous wounds. Wound healing experiments were also performed in transgenic mice. RESULTS - Oral wounds resolved faster than skin wounds in same person. RNA-sequencing, Gene Ontology, IPA and histological studies using oral and skin samples in stable state and during wound healing revealed significantly different patterns in gene expression, molecular function and biological process, especially keratinization, epidermal cell differentiation, responses to biotic stimulus, and inflammation. We identified a unique expression of the SOX2 and PITX1 transcriptional regulators that confer a specific identity on oral keratinocytes. In vitro, SOX2 and PITX1 had the potential of reprogramming skin keratinocytes to acquire increased cell migration capability and improve wound resolution. Lastly, skin wound healing was promoted in SOX2 overexpressing mouse (K14CreERTM/LSL-SOX2). CONCLUSIONS - We present a unique combination of human clinical data, histological and gene expression analysis, and mouse wound healing date. This information has been essential in determining the molecular anatomy of the wound healing process in oral and skin epithelia.
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