Both Wnt signaling and epidermal stem cell-derived extracellular vesicles are involved in epidermal cell growth
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Both Wnt signaling and epidermal stem cell-derived extracellular vesicles are involved in epidermal cell growth Ling Leng1*† , Jie Ma2†, Luye Lv3†, Wenjuan Wang4, Dunqin Gao1, Yunping Zhu2,5 and Zhihong Wu1
Abstract Millions suffer from skin diseases. Functional interfollicular epidermal stem cells are needed in skin therapy or drug screening in vitro. We obtained functional interfollicular epidermal stem cells with intact stemness and cell junctions by treating them with Wnt3a. Moreover, epidermal stem cell-derived extracellular vesicles were useful in epidermal cell growth. Finally, functional epidermal 3D organoids with polarity were cultured using Wnt3a and the supernatant derived from interfollicular epidermal stem cells and fresh medium in a 1:1 ratio. These results provide novel directions for the improvement of skin organoids and their potential in clinical application. Keywords: Epidermal stem cell, Extracellular vesicle, Organoids, Proteomics, Epidermal development, Extracellular matrix
Background In mammals, several distinct cell populations of the skin comprise three basic layers—epidermal layer, dermal layer, and hypodermis or subcutaneous fat layer. The epidermis is the outermost layer, composed of stratified cell layers maintained by keratinocytes, including both stem cells and the mature cells in abundance. The basal layer of the epidermis has undifferentiated proliferative progenitor cells expressing keratins, including keratin 5 (K5) and keratin 14 (K14) [1]. These progenitors not only replenish the basal layer through self-renewal, but also progressively migrate upwards through the epidermis, differentiating to form mature keratinocytes expressing keratin 1 (K1), keratin 10 (K10), and involucrin, and finally the outer layers of the terminally differentiated, dead stratum corneum cells [2]. Skin homeostasis * Correspondence: [email protected]; [email protected] † Ling Leng, Jie Ma and Luye Lv contributed equally to this work. 1 Stem Cell and Regenerative Medicine Lab, Department of Medical Science Research Center, Translational Medicine Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China Full list of author information is available at the end of the article
needs two types of epidermal stem cells (EpSCs) including interfollicular epidermal stem cells and hair follicle stem cells. After injury, the interfollicular epidermal stem cells replicate and differentiate to form the mature epidermis and regenerate hair follicles. Wnt signaling pathways are involved in the maintenance of both the two types of stem cells, and play an essential role during skin development [2, 3]. Besides, the Wnt signaling pathways are important during wound healing [4] and regulate epidermal cell proliferation of skin EpSCs [5]. Canonical Wnt proteins result in the accumulation of unphosphorylated β-catenin protein stability by inhibiting GSK3β kinase [6], and β-catenin activates as a nuclear cofactor for the LEF1/T
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