Abstract
While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown. A lipidomic analysis of primary human keratinocytes revealed accumulation of numerous lipid species during suspension-induced differentiation. A small interfering RNA screen of 258 lipid-modifying enzymes identified two genes that on knockdown induced epidermal differentiation: ELOVL1, encoding elongation of very long-chain fatty acids protein 1, and SLC27A1, encoding fatty acid transport protein 1. By intersecting lipidomic datasets from suspension-induced differentiation and knockdown keratinocytes, we pinpointed candidate bioactive lipid subspecies as differentiation regulators. Several of these-ceramides and glucosylceramides-induced differentiation when added to primary keratinocytes in culture. Our results reveal the potential of lipid subspecies to regulate exit from the epidermal stem cell compartment.
Highlights
While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown
The predominant lipid species change across the different epidermal layers, with the basal and spinous layers enriched in more polar lipid classes such as phospholipids and sphingomyelins, the granular layers exhibiting higher levels of glycosylceramides and cholesterol sulfates, and the cornified layer mostly composed of cholesterol, fatty acids, and ceramides, ω-acylceramides that are only found in the outermost epidermal layer [14]
None of the other lipid classes showed such a marked change with time in suspension, it was notable that several families were affected by PKC inhibition (SI Appendix, Fig. S1A)
Summary
While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown. These cells migrate from the basal layer, home of the stem cell compartment, upward toward the surface of the skin through the spinous and granular layers to reach the cornified layer During this migration, keratinocytes undergo a terminal differentiation process, accumulating transglutaminase-cross-linked proteins and secreting lamellar bodies enriched in highly hydrophobic lipid species. The predominant lipid species change across the different epidermal layers, with the basal and spinous layers enriched in more polar lipid classes such as phospholipids and sphingomyelins, the granular layers exhibiting higher levels of glycosylceramides and cholesterol sulfates, and the cornified layer mostly composed of cholesterol, fatty acids, and ceramides, ω-acylceramides that are only found in the outermost epidermal layer [14] These differences are the cumulative result of keratinocyte lipid metabolism, sebaceous gland secretion, and microbial production [10, 12, 15]. Several studies suggest tight regulation and diverse functions for specific lipid molecular structures in a variety of cellular processes, ranging from cell division [23] to the innate immune response [24]
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