A team of international scientists led by Gioele La Manno, PhD, and Giovanni D’Angelo, PhD, at Ecole Polytechnique Federale De Lausanne (EPFL) have reportedly found for the first time that one of the internal factors is too crucial for fate of a cell is its production of lipids. The researchers published their study (“Sphingolipids control dermal fibroblast heterogeneity”) in Science.
Working on skin fibroblasts, researchers combined two techniques to sort cells into lipid-producing profiles. They used high-resolution mass spectrometry imaging, which allowed them to visualize the distribution of specific lipids in each cell, and single-cell mRNA sequencing, which allowed them to determine the gene expression profile of each fibroblast — a sort of transcriptome ID — and each Classify cell into a transcriptional subpopulation.
“Human cells produce thousands of lipids that change during cell differentiation and can vary between individual cells of the same type. However, we are only beginning to characterize the function of these cell-to-cell differences in lipid composition. Here we measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging with single-cell transcriptomics,” the researchers write.
“We found that the cell-to-cell variations of specific lipid pathways contribute to the establishment of cellular states involved in the organization of skin architecture. Sphingolipid composition is shown to define fibroblast subpopulations, with sphingolipid metabolism rewiring driving cell-state transitions.
“Hence, cell-to-cell lipid heterogeneity affects the determination of cell states and adds a new regulatory component to the self-assembly of multicellular systems.”
The first thing the study revealed was that dermal fibroblasts can have multiple lipid groups, or lipid compositional states, which the researchers called lipotypes.
According to the authors, cell states are intermediate stages in the process of cell differentiation, where state changes precede final binding. But there was a clue: each lipotype corresponded to specific transcriptional subpopulations in vitro and to fibroblasts from different dermal layers of the skin in vivo.
Searched for biomarkers
The question now was which markers could be used to identify the different lipotypes. Given their correlation with fibroblast transcription sets, the researchers went on to isolate pathways that might be responsible for this association.
They found that the main markers of the different states of lipid composition are a family of fat molecules called sphingolipids, named after the mythical Sphinx. Sphingolipids are involved in cell-to-cell communication and protect the cell’s outer surface by forming barriers on its membrane.
At this point, the researchers discovered that the different lipotypes influence the cells’ different responses to external stimuli from their microenvironment, driving them into different cell fates, even when the two original cells were identical. In fact, the researchers found that it is possible to completely reprogram a cell’s fate simply by manipulating its sphingolipid composition.
In the latter part of the study, the team found that lipid composition and signaling pathways are wired into self-perpetuating circuits, and it is these circuits that are responsible for the differences in metabolism and gene transcription between fibroblasts.
The key molecule here is fibroblast growth factor or FGF2, a signaling protein involved in many processes such as B. embryonic development, cell growth, morphogenesis, tissue repair and even tumor growth and invasion. Related to this study, sphingolipids were found to regulate FGF2 signaling using two different types of sphingolipids that are both positive and negative regulators.
“We discovered an unexpected relationship between lipidomes and transcriptomes in single cells,” the authors write, referring to the full profile of a cell’s lipid production. “Lipidome remodeling could act as an early driver in the establishment of cell identity and, by following the pathways of lipid metabolism of individual cells, may have the potential to inform us about key mechanisms of cell fate decision-making. Thus, this study raises new questions about the role of lipids in cell fate decisions and adds a new regulatory component to the self-assembly of multicellular systems.”