Abstract
Amniotic epithelial stem cells (AESCs) are considered as potential alternatives to keratinocytes (KCs) in tissue-engineered skin substitutes used for treating skin damage. However, their clinical application is limited since similarities and distinctions between AESCs and KCs remain unclear. Herein, a transcriptomics analysis and functional evaluation were used to understand the commonalities and differences between AESCs and KCs. RNA-sequencing revealed that AESCs are involved in multiple epidermis-associated biological processes shared by KCs and show more similarity to early stage immature KCs than to adult KCs. However, AESCs were observed to be heterogeneous, and some possessed hybrid mesenchymal and epithelial features distinct from KCs. A functional evaluation revealed that AESCs can phagocytose melanosomes transported by melanocytes in both 2D and 3D co-culture systems similar to KCs, which may help reconstitute pigmented skin. The overexpression of TP63 and activation of NOTCH signaling could promote AESC stemness and improve their differentiation features, respectively, bridging the gap between AESCs and KCs. These changes induced the convergence of AESC cell fate with KCs. In future, modified reprogramming strategies, such as the use of small molecules, may facilitate the further modulation human AESCs for use in skin regeneration.
Highlights
Skin damage is a major cause of global disease burden, affecting millions worldwide [1]
The upregulated genes in Amniotic epithelial stem cells (AESCs) were significantly enriched in 52, 16, and 9 gene ontology (GO) terms associated with biological process (BP), cellular component (CC), and molecular function (MF), respectively
The corresponding number of enriched GO terms for the upregulated genes in KCs was 48, 11, and 9, respectively (Figure 1b). Intersection analyses between these corresponding groups were performed, which revealed 7, 4, and 2 terms associated with BP, CC, and MF, respectively, which were shared by both AESCs and KCs (Figure 1b, Table 1)
Summary
Skin damage is a major cause of global disease burden, affecting millions worldwide [1]. Autologous skin sources are extremely limited and cannot satisfy the high demand. Tissue-engineered skin substitutes can be used to treat acute and chronic skin wounds and can enhance wound healing, reduce inflammatory response, and provide safe coverage [2]. Keratinocytes (KCs), which are primary cells of the epidermis in human skin, are commonly used in tissue engineered skin substitutes and function to synthesize keratin, exerting a protective role [3]. Autologous KCs are quite limited in quantity and require a long time to prepare and be used as skin substitutes in patients with skin damage. The usage of allogeneic KCs can address these issues, other factors such as graft rejection and possible disease transmission still hinder the development and application of skin substitutes
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