Single Cell mass spectrometry: Towards quantification of small molecules in individual cells

Abstract

Studying cell heterogeneity can provide a deeper understanding of biological activities, but appropriate studies cannot be performed using traditional bulk analysis methods. The development of diverse single cell bioanalysis methods is in urgent need and of great significance. Mass spectrometry (MS) has been recognized as a powerful technique for bioanalysis for its high sensitivity, wide applicability, label-free detection, and capability for quantitative analysis. In this review, the general development of single cell mass spectrometry (SCMS) field is covered. First, multiple existing SCMS techniques are described and compared. Next, the development of SCMS field is discussed in a chronological order. Last, the latest quantification studies on small molecules using SCMS have been described in detail.

Keywords: Ambient techniques; Cell heterogeneity; High throughput; Quantitative analysis; Single cell mass spectrometry; Single cell metabolomics; Vacuum-based techniques.

Fig. 1.

Vacuum-based SCMS methods using (A) SIMS (secondary ion MS), (B) GCIB-SIMS (gas cluster ion beam-secondary ion mass spectrometry) (C) MALDI (matrix-assisted laser desorption/ionization) and (D) matrix-free LDI (laser desorption/ionization).

Fig. 2.

Ambient SCMS methods based on (A) nano-ESI emitter, (B) cell pressure probe, (C) electroosmotic extraction, (D) the T-probe, (E) the Single-probe, (F) Nano-DESI (nano desorption electrospray ionization), (G) droplet extraction, (H) DESI (nano desorption electrospray ionization), (I) LAESI (laser ablation electrospray ionization), and (J) cell electro-migration and electroporation.

Fig. 3.

Quantitative ambient SCMS methods with different cell separation techniques. (A) Dean flow fractionation. Left panel: Top view of the microfluidic device. Right panel: cross-section views of different regions of device: (1) the inlet, (2) vortex inside the curved channel, and (3) outlet. (B) SCP (Single-cell printer) coupled to LVC (liquid vortex capture) device. Schematic shows the cross-section views of SCP and LVC devices.