Stem cells and extracellular vesicles to improve preclinical orofacial soft tissue healing

Orofacial soft tissue wounds caused by surgery for congenital defects, trauma, or disease frequently occur leading to complications affecting patients' quality of life. Scarring and fibrosis prevent proper skin, mucosa and muscle regeneration during wound repair. This may hamper maxillofacial growth and speech development. To promote the regeneration of injured orofacial soft tissue and attenuate scarring and fibrosis, intraoral and extraoral stem cells have been studied for their properties of facilitating maintenance and repair processes. In addition, the administration of stem cell-derived extracellular vesicles (EVs) may prevent fibrosis and promote the regeneration of orofacial soft tissues. Applying stem cells and EVs to treat orofacial defects forms a challenging but promising strategy to optimize treatment. This review provides an overview of the putative pitfalls, promises and the future of stem cells and EV therapy, focused on orofacial soft tissue regeneration

Retinoic acid signalling in the development of the epidermis, the limbs and the secondary palate

Retinoic acid (RA), the active derivative of vitamin A, is one of the major regulators of embryonic development, including the development of the epidermis, the limbs and the secondary palate. In the embryo, RA levels are tightly regulated by the activity of RA synthesizing and degrading enzymes. Aberrant RA levels due to genetic variations in RA metabolism pathways contribute to congenital malformations in these structures. In vitro and in vivo studies provide considerable evidence on the effects of RA and its possible role in the development of the epidermis, the limbs and the secondary palate. In conjunction with other regulatory factors, RA seems to stimulate the development of the epidermis by inducing proliferation and differentiation of ectodermal cells into epidermal cells. In the limbs, the exact timing of RA location and level is crucial to initiate limb bud formation and to allow chondrogenesis and subsequent osteogenesis. In the secondary palate, the correct RA concentration is a key factor for mesenchymal cell proliferation during palatal shelf outgrowth, elevation and adhesion, and finally to allow bone formation in the hard palate. These findings are highly relevant to understanding the mechanism of RA signalling in development and in the aetiology of specific congenital diseases.publisher: Elsevier articletitle: Retinoic acid signalling in the development of the epidermis, the limbs and the secondary palate journaltitle: Differentiation articlelink: http://dx.doi.org/10.1016/j.diff.2016.05.001 content_type: article copyright: © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.status: publishe

Effects of retinoic acid on proliferation and gene expression of cleft and non-cleft palatal keratinocytes

Retinoic acid (RA) is a key regulator of embryonic development and linked to several birth defects including cleft lip and palate (CLP). The aim was to investigate the effects of RA on proliferation and gene expression of human palatal keratinocytes (KCs) in vitro.status: publishe

Cytokine levels in crevicular fluid are less responsive to orthodontic force in adults than in juveniles

OBJECTIVES: Bone remodelling during orthodontic tooth movement is related to the expression of mediators in gingival crevicular fluid (GCF). No information is available concerning the effect of age on the levels of these mediators in GCF. The purpose of this study was to quantify three mediators (prostaglandin E2, interleukin-6 and granulocyte-Macrophage Colony-Stimulating Factor) in GCF during orthodontic tooth movement in juveniles and adults. MATERIAL AND METHODS: A total of 43 juvenile patients (mean age 11 +/- 0.7 year), and 41 adult patients (mean age 24 +/- 1.6 year) took part in the study. One of the lateral incisors of each patient was tipped labially, the other served as control. GCF samples were taken before force activation (t0) and 24 h later (t24). Mediator levels were determined by radioimmunoassay (RIA). RESULTS: PGE2 concentrations were significantly elevated at t24 in juveniles and adults, while concentrations of IL-6 and GM-CSF were significantly elevated only in juveniles. Total amounts of all three mediators in GCF significantly increased at t24 in both groups. CONCLUSIONS: In early tooth movement, mediator levels in juveniles are more responsive than levels in adults, which agrees with the finding that the initial tooth movement in juveniles is faster than in adults and starts without delay

Deregulated Adhesion Program in Palatal Keratinocytes of Orofacial Cleft Patients

Orofacial clefts (OFCs) are the most frequent craniofacial birth defects. An orofacial cleft (OFC) occurs as a result of deviations in palatogenesis. Cell proliferation, differentiation, adhesion, migration and apoptosis are crucial in palatogenesis. We hypothesized that deregulation of these processes in oral keratinocytes contributes to OFC. We performed microarray expression analysis on palatal keratinocytes from OFC and non-OFC individuals. Principal component analysis showed a clear difference in gene expression with 24% and 17% for the first and second component, respectively. In OFC cells, 228 genes were differentially expressed (p < 0.001). Gene ontology analysis showed enrichment of genes involved in β1 integrin-mediated adhesion and migration, as well as in P-cadherin expression. A scratch assay demonstrated reduced migration of OFC keratinocytes (343.6 ± 29.62 μm) vs. non-OFC keratinocytes (503.4 ± 41.81 μm, p < 0.05). Our results indicate that adhesion and migration are deregulated in OFC keratinocytes, which might contribute to OFC pathogenesis.status: publishe

Strategies to improve regeneration of the soft palate muscles after cleft palate repair

Children with a cleft in the soft palate have difficulties with speech, swallowing, and sucking. These patients are unable to separate the nasal from the oral cavity leading to air loss during speech. Although surgical repair ameliorates soft palate function by joining the clefted muscles of the soft palate, optimal function is often not achieved. The regeneration of muscles in the soft palate after surgery is hampered because of (1) their low intrinsic regenerative capacity, (2) the muscle properties related to clefting, and (3) the development of fibrosis. Adjuvant strategies based on tissue engineering may improve the outcome after surgery by approaching these specific issues. Therefore, this review will discuss myogenesis in the noncleft and cleft palate, the characteristics of soft palate muscles, and the process of muscle regeneration. Finally, novel therapeutic strategies based on tissue engineering to improve soft palate function after surgical repair are presented

Evaluation of a collagen-glycosaminoglycan dermal substitute in the dog palate.

Contains fulltext : 52041.pdf (publisher's version ) (Closed access)Tissue shortage complicates surgery of cleft lip and palate. The healing of defects on the palate impairs growth of the dentoalveolar complex because of scar tissue formation. Implantation of a matrix into the wound might overcome this adverse effect. Integra with and without a silicone top layer was implanted into standardized full-thickness wounds (O 6 mm) in the palatal mucoperiosteum in beagle dogs. In some wounds, the silicone layer was removed after 14 days. Control wounds did not have an implant. At 2 and 4 weeks post-surgery, the wounds were assessed for epithelialization, inflammation (hematoxylin and eosin, leucocyte protein L1), number of myofibroblasts (alpha smooth muscle actin), and general histological characteristics. Wounds filled with Integra without the silicone layer showed fewer myofibroblasts and inflammatory cells than the sham wounds. Collagen fibers were more randomly orientated in these wounds than in the sham group. Wound closure was found to be retarded, and many inflammatory cells were present when Integra with silicone was implanted. The silicone layer was lost within 4 weeks in these wounds. We conclude that, in the moist oral environment, the silicone of Integra is not required. Re-epithelialization and tissue integration proceed more favorably without it. Further research in the dentoalveolar development with Integra will be conducted in a simulated cleft palate repair in the dog model