Enhanced wound healing of tissue-engineered human corneas through altered phosphorylation of the CREB and AKT signal transduction pathways
| Autor: | Lucie Germain, Pascale Desjardins, Sylvain L. Guérin, Karine Zaniolo, Camille Couture |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MAP Kinase Signaling System Biomedical Engineering CREB Biochemistry Cornea Biomaterials Extracellular matrix Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Phosphorylation Cyclic AMP Response Element-Binding Protein Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cell Nucleus Wound Healing Tissue Engineering integumentary system biology Chemistry Gene Expression Profiling 3T3 Cells General Medicine Cell biology 030104 developmental biology medicine.anatomical_structure Microscopy Fluorescence 030221 ophthalmology & optometry biology.protein Signal transduction Wound healing Proto-Oncogene Proteins c-akt Signal Transduction Biotechnology |
| Zdroj: | Acta Biomaterialia. 73:312-325 |
| ISSN: | 1742-7061 |
| DOI: | 10.1016/j.actbio.2018.04.021 |
| Popis: | The cornea is a transparent organ, highly specialized and unique that is continually subjected to abrasive forces and occasional mechanical or chemical trauma because of its anatomical localization. Upon injury, the extracellular matrix (ECM) rapidly changes to promote wound healing through integrin-dependent activation of specific signal transduction mediators whose contribution is to favor faster closure of the wound by altering the adhesive and migratory properties of the cells surrounding the damaged area. In this study, we exploited the human tissue-engineered cornea (hTECs) as a model to study the signal transduction pathways that participate to corneal wound healing. By exploiting both gene profiling and activated kinases arrays, we could demonstrate the occurrence of important alterations in the level of expression and activation of a few mediators from the PI3K/Akt and CREB pathways in response to the ECM remodeling taking place during wound healing of damaged hTECs. Pharmacological inhibition of CREB with C646 considerably accelerated wound closure compared to controls. This process was considerably accelerated further when both C646 and SC79, an Akt agonist, were added together to wounded hTECs. Therefore, our study demonstrate that proper corneal wound healing requires the activation of Akt together with the inhibition of CREB and that wound healing in vitro can be altered by the use of pharmacological inhibitors (such as C646) or agonists (such as SC79) of these mediators. Statement of significance Corneal wounds account for a large proportion of all visual disabilities in North America. To our knowledge, this is the first time that a tissue-engineered human cornea (hTEC) entirely produced using normal untransformed human cells is used as a biomaterial to study the signal transduction pathways that are critical to corneal wound healing. Through the use of this biomaterial, we demonstrated that human corneal epithelial cells engaged in wound healing reduce phosphorylation of the signal transduction mediator CREB while, in the mean time, they increase that of AKT. By increasing the activation of AKT together with a decrease in CREB activation, we could considerably reduce wound closure time in our punch-damaged hTECs. Considering the increasing interest given to the reconstruction of different types of tissues, we believe these results will have a strong impact on the field of tissue-engineering and biomaterials. Altering the activation status of the Akt and CREB proteins might prove to be a therapeutically interesting avenue and may also find applications in wound healing of other tissues beside the cornea, such as the skin. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect