Electro-seq – multimodal charting of molecular and functional cell states via in situ RNA electro-sequencing

Paired mapping of single-cell gene expression and electrophysiology is essential to understand gene-to-function relationships in electrogenic tissues. Harvard University researchers have developed in situ electro-sequencing (electro-seq) that combines flexible bioelectronics with in situ RNA sequencing to stably map millisecond-timescale electrical activity and profile single-cell gene expression from the same cells across intact biological networks, including cardiac and neural patches. When applied to human-induced pluripotent stem-cell-derived cardiomyocyte patches, in situ electro-seq enabled multimodal in situ analysis of cardiomyocyte electrophysiology and gene expression at the cellular level, jointly defining cell states and developmental trajectories. Using machine-learning-based cross-modal analysis, in situ electro-seq identified gene-to-electrophysiology relationships throughout cardiomyocyte development and accurately reconstructed the evolution of gene expression profiles based on long-term stable electrical measurements. In situ electro-seq could be applicable to create spatiotemporal multimodal maps in electrogenic tissues, potentiating the discovery of cell types and gene programs responsible for electrophysiological function and dysfunction.

In situ electro-seq platform

(A) Schematics summarizing the in situ electro-seq method. (B) Representative photograph of flexible mesh electronics. Inset: schematic illustrates the multilayer structure of the electronics. (C) Overlapped fluorescence and bright-field (BF) image of a pair of binary E-barcodes highlighted in red box in (B). (D) Electrochemical impedance and phase from 0.1 to 10 kHz of a representative electrode. (E and F) Electrochemical impedance at 1 kHz across five different samples (E) and over 2 months of incubation (F). Values are mean ± SEM. (G) In situ sequencing of a cell-electronics hybrid. (H) Representative images of five rounds of sequencing overlaid with E-barcode. X, unknown base; red underline, decoded sequence; Ch1 to Ch4, fluorescence channels; E-barcodes labeled with R6G.
Li Q, Lin Z, Liu R, Tang X, Huang J, He Y, Sui X, Tian W, Shen H, Zhou H, Sheng H, Shi H, Xiao L, Wang X, Liu J. (2023) Multimodal charting of molecular and functional cell states via in situ electro-sequencing. Cell 186(9):2002-2017.[article]

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