SDF-1 Accelerates Skin Regeneration Via Recruitment Of Epidermal Stem Cells

Skin integrity is of importance for the protection and separation of body tissues from the surrounding environment. The loss of skin due to burns or trauma exposes the body to severe stress, impairing or even eliminating the many vital functions this organ performs. The epidermis is a multilayered structure that comprises of stratum basale, Stratum spinosum, Stratum granulosum, Stratum Lucidum and Stratum corneum. Keratinocytes are shed from the surface of the skin and must be replaced throughout life. Regular replacement is achieved as epidermal stem cell in the basal layer of the epidermis give rise to progeny that exit the cell cycle and differentiate as they are displaced toward the surface of the skin. The prevailing paradigm to explain the growth and homeostasis of the epidermis is the epidermal proliferating unit (EPU) model. Epidermal stem cells have extensive capacity for self-renewal. The stem cells generate a"transient amplifying"population with more limited proliferative capacity. The TA cells can regenerate themselves and also give rise to the more differentiated keratinocytes that are displaced from the basement membrane and form the superficial layers of the epidermis.When the epidermis is damaged, keratinocytes from the epidermis surrounding the wound are mobilized to regenerate an epidermal barrier. Keratinocytes invade the wound surface and generate a thickened and hyperproliferative epithelium that then gradually reverts to a more normally organized stratified epidermis. The participation of epidermal stem cell in wound healing has been well documented.Stromal cell–derived factor-1(SDF-1) originally cloned from a stromal cell line as a pre-B-cell growth-stimulating factor, which is a highly conserved chemokine belong to the family of chemotactic cytokines, with a low molecular mass (8-10 kDa). SDF-1 is the only known ligand for the G-coupled CXCR4 receptor [10]. Due to no known overlapping membrane proteins that bind to SDF-1, then inhibition of CXCR4 signaling has similar effects to inhibition of SDF-1 functions. Tissue repair and regeneration after injury is thought to involve the selective recruitment of circulating or resident stem cell populations. Chemokine/chemokine receptor interactions are expected to contribute to these mechanisms of stem cell plasticity. However, only one chemokine/chemokine receptor interaction, the SDF-1α/CXCR4 interactions are expected to contribute these mechanisms of stem cell plasticity. However, only one chemokine/chemokine receptor interaction, the SDF-1α/CXCR4 interaction has thus far been reported. The SDF-1α/CXCR4 interaction has been identified as a factor causing hematopoietic stem cell mobilization, however, other tissue cells are recruited from the bone marrow(BM) cell by this interaction, including myocytes and neural cell , in addition, SDF-1αand CXCR4 are widely expressed on various cell types and SDF-1α/CXCR4 interactions play an important role in several developmental and regenerative phenomena, such as cardiogenesis, neovascularization , hematopoiesis, and hepatic development.Here we show that stem cell attracting chemokine SDF-1 is the major regulator involved in the migration of epidermal stem cells from basal layer into wound. By screen chemokine SDF-1 expression in burn blister fluid and wound margin at different time phase. We show that following the hurt, the levels of SDF-1 is markedly increased first in the burn blister and then in the wound margin. However, 9 days after hurt, SDF-1 was not detected in the wound margin. To confirm that SDF-1 was actually functional in epidermal stem cells, in vitro chemotaxis assays were undertaken. In order to further show SDF-1 is the regulator involved in the migration of epidermal stem cells in vivo, the mice were anesthetized and 6-mm full-thickness punch biopsy wounds were made by folding the back skin, and were injected SDF-1, AMD3100 (the specific antagonist of CXCR4) and stroke-physiological saline solution. The results demonstrate that the SDF-1 is a regulator involved in the migration of epidermal stem cells in vitro and vivo, and increased epidermal stem cells migration caused by SDF-1 significantly accelerated the wound healing process, and the effect can be blocked by AMD3100.These results provide direct evidence that recruitment of epidermal stem cell to the wound is regulated by SDF-1/CXCR4 interactions, which makes possible the development of new regenerative therapeutic strategies.