Single-Cell Metabolomics by Mass Spectrometry: Opportunities and Challenges

Abstract

Cellular heterogeneity is an inherent property of cell populations with a wide spectrum of biological manifestations, ranging from barely observable variations that enhance organismal adaptation, to life-threatening differences. Single-cell metabolomics can reveal molecular information and variations in metabolite concentrations between cells that are masked in cell-population studies. These differences are quantitatively captured by the abundance distributions for the population and their statistical analysis can reveal the presence of latent subpopulations. In recent years, mass spectrometry (MS), combined with novel sampling and ionization techniques, has become an important tool for single-cell metabolomics. These new techniques must contend with significant challenges in the form of small cell sizes and volumes, ultratrace metabolite amounts per cell, and potentially interfering high turnover rates and rapid diffusion. Owing to the ultrasmall sample volume, low abundance of some metabolites, and poor ionization efficiencies, metabolite detection, identification, and accurate quantitation remain a major challenge. The ability of some techniques to analyze tissue-embedded cells opens the door for spatial metabolomics, potentially revealing cellular synergism in organ level metabolism. In this Concept article, we present a bird's eye view of these major themes in single cell metabolomics and some of the relevant MS-based methods.