Signaling pathways and molecular markers of epidermal stem cells during regeneration

Abstract

Regenerative medicine is a relatively new and very promising branch of modern medicine, which combines both the theoretical knowledge about reparative and regenerative mechanisms of epithelial cells and the practical knowledge about factors regulating this process. Thus, regenerative medicine can significantly expand the capabilities of clinicians. In our review, we present results of molecular and genetic studies on effects of epidermal stem cells on epithelial repair and regeneration. During regeneration, injury-activated immune cells induce wound healing, extracellular matrix remodeling, migration, dedifferentiation, and/or proliferation followed by differentiation of somatic or stem cells. The anti-inflammatory response stops the regenerative process, which ends with tissue remodeling to achieve the original functional state. It is noteworthy that many of these processes are associated with increased glycolysis. Therefore, the peroxisome proliferator-activated receptor (PPAR) β/δ, which is known to be involved in lipid catabolism, glucose homeostasis, inflammation, proliferation, differentiation, and regeneration in mammalian skin, bone and liver, is a promising target for stimulating regeneration in mammals. This review summarizes the current knowledge of PPAR β/δ involvement in the processes related with wound healing and regeneration. The cited literature includes reports of possible molecular signaling pathways that cause changes in the processes of migration, proliferation and differentiation of epithelial cells and in the expression of integrins, keratin, a number of microRNAs, and long noncoding RNAs. The review addresses effects of the microenvironment, specifically, via activation of Wnt and Notch (intracellular) signaling systems, which serve as important regulatory components of the stem cell microenvironment. The functioning of the Wnt and Notch systems is essential for wound healing. The epigenetic regulation of epidermal regeneration is discussed. The review presents the mechanisms mediated by PcG-active proteins of the growth factor and changes in the activities of histone demethylases, histone deacetylases, and DNA methyltransferases. Information is provided about the ATP-dependent chromatin remodeling by proteins of the SNF2 family (including SWI2 / SNF2 (BRG1 / BRM), ISWI and CHD / Mi-2β), BRG1 and JMJD3) and their influence on differentiation and the activity of epidermal stem cells.