Single Cell in situ lipidomics reveals a role for cell-to-cell sphingolipid heterogeneity in the maintenance of cell identity
Eukaryotic cells produce thousands of lipids each potentially contributing to specific biological functions. With the development of lipidomics we now appreciate the lipid compositional complexity of the cell, and start making sense of lipidome dynamics. Lipidomes indeed vary among cell types and are reprogrammed in differentiation events. Moreover, lipid composition is subjected to cell-to-cell variation in otherwise homogeneous cell populations suggesting that lipid heterogeneity contributes to the emergence of multicellular patterns. Lipid biologists have mostly addressed lipidomes in bulk cell extracts or selected lipids at the single-cell level. Thus, how lipidomes vary form one cell to another and which cell-to-cell lipid variations have biological meaning remains to be defined. Here by using high-resolution mass spectrometry imaging, we have analyzed a sizable fraction of the lipidome of hundreds of individual human dermal fibroblasts. By this approach we found that: (i) specific lipid metabolic segments are subjected to high cell-to-cell variability; (ii) specific lipid configurations mark discrete cell states; (iii) highly variable lipids participate in the maintenance of fibroblast states involved in wound healing and associated with tumor-promoting microenvironment. These data reveal a dominant role for specific cell lipotypes in the determination of cell identity in tissue homeostasis and in its pathological perturbations.