Sphingolipid Control of Fibroblast Heterogeneity Revealed by Single-Cell Lipidomics

Abstract

Human cells produce thousands of lipids that impact a wide range of biological processes in ways we are only starting to characterize. The cellular composition in lipids changes during differentiation events and also varies across individual cells of the same type. Yet, the precise differences in lipid composition that directly affect cell phenotypes remain unknown. Here we have measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging to single-cell transcriptomics. We found that the cell-to-cell variation of specific lipid metabolic pathways contributes to the establishment of cell states involved in wound repair and in skin cancer growth. Sphingolipid composition defined fibroblast subpopulations while sphingolipid metabolic rewiring drove cell state transitions. These data uncover a role for cell-to-cell lipid heterogeneity in the determination of cell states and reveal a new regulatory component to the homeostasis and self-organization of multicellular systems.

Mammalian Epidermis: A Compendium of Lipid Functionality

“…Technological advances will be key to answering these complex questions. In this respect, implementation of recently developed, sophisticated techniques, like single-cell lipidomics ( Capolupo et al, 2021 ; Li et al, 2021 ), already promises more exciting developments in unraveling the finer details of the roles played by lipids in the regulation of cellular behavior ( Züllig et al, 2020 ; Capolupo et al, 2021 ; Li et al, 2021 ). We are confident that in the future the application of these new technologies will provide a clearer picture of the rich and essential contribution of lipid molecules to epidermal biology.…”

Integratomics of Human Dermal Fibroblasts Treated with Low Molecular Weight Hyaluronic Acid

“…Among the lipid classes in the skin, sphingolipids and ceramides are among the most important functional molecules at the stratum corneum and deeper fibroblasts layer, and they play a crucial role in the formation and maintenance of the skin barrier integrity [ 16 , 17 , 18 ]. Moreover, ceramides are necessary to link corneocytes into a waterproof barrier and enhance skin hydration that has an impact on cell morphology at the surface and deeper layers of the epidermis.…”

“…Sphingolipid composition can influence the identity, transition path and, lipid metabolic pathway in the establishment of wound repair of fibroblasts [ 18 ]. Nevertheless, being their activity depended on cell type and belonged subclasses, sphingolipids were further classified according to their structure, obtaining 43 (41%) non-hydroxy-sphingosine-ceramides, 26 (25%) sphingadienine-ceramides, 19 (18%) dihydro-ceramides, 10 (10%) phyto-ceramides, 6 (6%) deoxy-ceramides, and one (1%) dihydro-deoxy-ceramides, in line with what previously demonstrated [ 16 , 19 ].…”

How Does Liquid-Liquid Phase Separation in Model Membranes Reflect Cell Membrane Heterogeneity?

“…Besides revealing the potentials and limitations of existing technologies, combining new technologies will also be instrumental to unravel the mysteries of biomembranes in the future. Lipidomics has recently gained popularity, and the most recent singlecell lipidomics approach has the potential to be a game-changer [118]. Super-resolution microscopy approaches and chemical biology tools are becoming constantly better.…”