Abstract
Skin epidermal stem cells (EpSCs) play critical roles in skin homeostasis and the repair of skin injury. Luteolin-7-glucoside (L7G) has been reported to accelerate skin wound healing through its anti-inflammatory and antioxidative activity. But its effect on EpSCs is not clear. In the present study, we examined the effect of L7G on the proliferation of human EpSCs and explored the mechanisms involved. MTT assay showed that L7G promoted EpSC proliferation in a dose- and time-dependent manner. BrdU incorporation assay and Ki67 immunofluorescence staining confirmed the proproliferative effect of L7G on EpSCs. Cell cycle analysis showed that treatment of EpSCs with L7G decreased the cell number in the G1 phase and increased the cell number in the S phase. In addition, L7G significantly enhanced EpSC migration. Mechanistic studies showed that L7G significantly induced the expression of β-catenin and c-Myc, as well as cyclins D1, A2, and E1 which are critical for G1/S phase transition. L7G stimulated EpSC proliferation through β-catenin and c-Myc. We further examined the effect of L7G on EpSC proliferation in skin tissues by treatment of human skin explants with L7G and examined the number of EpSCs by immunohistochemical stain of EpSC markers α6 integrin and β1 integrin. We found that treatment of human skin tissue explants with L7G significantly increased the thickness of the epidermis and increased the numbers of α6 integrin-positive and β1 integrin-positive cells at the basal layer of the epidermis. Taken together, these results indicate that L7G promotes EpSC proliferation through upregulating β-catenin, c-Myc, and cyclin expression. L7G can be used to expand EpSCs for generating epidermal autografts and engineered skin equivalents.
Highlights
Epidermal stem cells (EpSCs) residing in the basal layer of the epidermis play a vital role in epidermal regeneration, skin homeostasis, and wound healing [1, 2]
Human EpSCs were selected from epidermal keratinocyte suspension according to their rapid attachment to collagen type IV [18, 19]
FACS analysis showed that these cells expressed high levels mCofDaαr7k61slionowtfeiEgsrphiSnigChasen[rd1t9hlo,a2wn09]le.0vT%ehl(seFopigfoupCrueDl1a7t(1ibo,)nt)w. oWof iewnaetellslg-orrieencxoaαgm6nhiiingzhee/ddthe expression of β1 integrin and CK19, another two markers of EpSCs, by immunofluorescence staining, and found that more than 90% of the cells are β1 integrin and CKl9 positive (Figure 1(c))
Summary
Epidermal stem cells (EpSCs) residing in the basal layer of the epidermis play a vital role in epidermal regeneration, skin homeostasis, and wound healing [1, 2]. When the skin is injured, the EpSCs around the wound are activated to proliferate, the progeny migrate to the wound site and differentiate to regenerate the epidermis [3,4,5]. Wnt signaling [6] and Wnt/β-catenin signaling plays an important role in the proliferation of skin EpSCs [6, 7]. Other signalings contribute to EpSC proliferation, such as integrin-MAP kinase- and Notch-related signaling pathways [8, 9]. EpSCs are becoming important sources for novel therapeutic approaches in the management of wounds. Transplantation of cultured keratinocytes which contain EpSCs, either in cell suspension or on various delivery systems, has been
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