Description
Single-cell genomics technologies record cellular heterogeneity at ever-increasing scale and resolution. However, they remain cell-destructive and require computational trajectory inference to reconstruct cellular dynamics. Prior work used gene expression similarity to estimate pseudotime, a simplified one-dimensional cell ordering. While this concept was successfully applied to well-characterized processes, it remains challenging to reconstruct trajectories for complex biological systems due to uncertain directions and complex dynamics.
With CellRank, we extend trajectory inference beyond well-characterized systems to gain insights into disease-relevant systems, including development, regeneration, reprogramming, and cancer. We achieve this by exploiting additional data modalities, like RNA velocity (La Manno et al., Nature 2018; Bergen et al., Nature Biotech 2020), metabolic labeling (Erhard et al., Nature 2019; Battich et al., Science 2020), spatial context, experimental time points (Schiebinger et al., Cell 2019), and lineage tracing information (Wagner et al., Nat. Rev. Gen., 2020).
License
The project operates under the BSD-3-Clause license, promoting open redistribution and usage with or without modifications.
Documentation
Detailed guidance and information are available in the official documentation, facilitating a deeper understanding of CellRank's applications and functionalities.
Publication
We demonstrate the success of our software in two publications:
- CellRank 1: published in Nature Methods (Lange et al. 2022), combined RNA velocity and gene expression similarity to predict state transitions.
- CellRank 2: available as a preprint on bioRxiv (Weiler et al. 2023) uses metabolic labels, spatial context, experimental time points, and lineage tracing information, to predict state transitions.
Contributors
The main contributors to the CellRank project are the members of the Theis Lab. You can find more about the team and their contributions on the GitHub page.
Key Applications
- Estimation of differentiation directions based on a variety of biological priors.
- Computation of initial, terminal, and intermediate macrostates.
- Inference of fate probabilities and driver genes.
- Visualization and clustering of gene expression trends.
Background and rationale
Important biological processes, including development, regeneration, and cancer, manifest as complex cellular state changes. Studying these processes holds enormous potential for many areas of medicine. Single-cell genomics (SCG) represents a promising toolset to gain insights into such processes as it can resolve individual molecular states. For example, single-cell RNA-sequencing (scRNA-seq) measures gene expression in single cells. However, scRNA-seq and related assays are destructive, representing a hurdle to link fate outcomes to molecular state changes. Thus, the main task of CellRank is to gain biological insights into dynamical cellular processes from SCG data.
Concrete challenges faced by prior methods include:
- Noise and high dimensionality: SCG data is extremely sparse, noisy, and high-dimensional.
- Non-directionality: SCG data only contains the state of each cell but no information about possible transitions.
- Large and complex datasets: SCG data has increased in size (millions of cells) and complexity (many modalities).
CellRank overcomes these challenges by (1) operating in latent spaces and aggregating over many cellular profiles in Markov chains, (2) estimating directionality from various experimental priors, (3) interfacing with optimized linear algebra libraries, and exploiting sparsity.
Contact
For bugs, help, or suggestions, feel free to open an issue or reach out via email at info@cellrank.org.
Should you have any specific inquiries regarding CellRank, please do not hesitate to reach out to Philipp Weiler at philipp.weiler@helmholtz-munich.de or to Marius Lange at marius.lange@helmholtz-munich.de