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Improving hard palate wound healing using immune modulatory autotherapies.

ABSTRACT: Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Despite this, injuries to the mucosal surface often heal faster than cutaneous wounds and leave less noticeable scars. Patients undergoing cleft palate repair have a high degree of wound healing complications with up to 60% experiencing oronasal fistula (ONF) formation. In this study, we developed a mouse model of hard palate mucosal injury, to study the endogenous injury response during oral cavity wound healing and ONF formation. Immunophenotyping of the inflammatory infiltrate following hard palate injury showed delayed recruitment of non-classical LY6Clo monocytes and failure to resolve inflammation. To induce a pro-regenerative inflammatory response, delivery of FTY720 nanofiber scaffolds following hard palate mucosal injury promoted complete ONF healing and was associated with increased LY6Clo monocytes and pro-regenerative M2 macrophages. Alteration in gene expression with FTY720 delivery included increased Sox2 expression, reduction in pro-inflammatory IL-1, IL-4 and IL-6 and increased pro-regenerative IL-10 expression. Increased keratinocyte proliferation during ONF healing was observed at day 5 following FTY720 delivery. Our results show that local delivery of FTY720 from nanofiber scaffolds in the oral cavity enhances healing of ONF, occurring through multiple immunomodulatory mechanisms. STATEMENT OF SIGNIFICANCE: Wound healing complications occur in up to 60% of patients undergoing cleft palate repair where an oronasal fistula (ONF) develops, allowing food and air to escape from the nose. Using a mouse model of palate mucosal injury, we explored the role of immune cell infiltration during ONF formation. Delivery of FTY720, an immunomodulatory drug, using a nanofiber scaffold into the ONF was able to attract anti-inflammatory immune cells following injury that enhanced the reepithelization process. ONF healing at day 5 following FTY720 delivery was associated with altered inflammatory and epithelial transcriptional gene expression, increased anti-inflammatory immune cell infiltration, and increased proliferation. These findings demonstrate the potential efficacy of immunoregenerative therapies to improve oral cavity wound healing.

SUBMITTER: Ballestas SA

PROVIDER: S-EPMC7685787 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Improving hard palate wound healing using immune modulatory autotherapies.

Ballestas Samir A SA Turner Thomas C TC Kamalakar Archana A Stephenson Yvonne C YC Willett Nick J NJ Goudy Steven L SL Botchwey Edward A EA

Acta biomaterialia 20190425

Oral cavity wound healing occurs in an environment that sustains ongoing physical trauma and is rich in bacteria. Despite this, injuries to the mucosal surface often heal faster than cutaneous wounds and leave less noticeable scars. Patients undergoing cleft palate repair have a high degree of wound healing complications with up to 60% experiencing oronasal fistula (ONF) formation. In this study, we developed a mouse model of hard palate mucosal injury, to study the endogenous injury response du ...[more]

PMID: 31029828

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Project description:BACKGROUND: The bulge region of the hair follicle contains resident epithelial stem cells (SCs) that are activated and mobilized during hair growth and after epidermal wounding. However, little is known about the signals that modulate these processes. Clinical and experimental observations show that a reduced supply of sensory innervation is associated with delayed wound healing. Since axon terminals of sensory neurons are among the components of the bulge SC niche, we investigated whether these neurons are involved in the activation and mobilization of the hair stem cells during wound healing. METHODOLOGY/PRINCIPAL FINDINGS: We used neonatal capsaicin treatment to reduce sensory terminals in the rat skin and performed morphometric analyses using design-based stereological methods. Epithelial proliferation was analyzed by quantifying the number of bromodeoxyuridine-labeled (BrdU(+)) nuclei in the epidermis and hair follicles. After wounding, the epidermis of capsaicin-treated rats presented fewer BrdU(+) nuclei than in control rats. To assess SC progeny migration, we employed a double labeling protocol with iododeoxyuridine and chlorodeoxyuridine (IdU(+)/CldU(+)). The proportion of double-labeled cells was similar in the hair follicles of both groups at 32 h postwounding. IdU(+)/CldU(+) cell proportion increased in the epidermis of control rats and decreased in treated rats at 61 h postwounding. The epidermal volume immunostained for keratin 6 was greater in treated rats at 61 h. Confocal microscopy analysis revealed that substance P (SP) and calcitonin gene-related peptide (CGRP) receptor immunoreactivity were both present in CD34(+) and BrdU-retaining cells of the hair follicles. CONCLUSIONS/SIGNIFICANCE: Our results suggest that capsaicin denervation impairs SC progeny egress from the hair follicles, a circumstance associated with a greater epidermal activation. Altogether, these phenomena would explain the longer times for healing in denervated skin. Thus, sensory innervation may play a functional role in the modulation of hair SC physiology during wound healing.

Dataset Information

Improving hard palate wound healing using immune modulatory autotherapies.

Publications

Improving hard palate wound healing using immune modulatory autotherapies.

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