sclsd: Latent Space Dynamics for Single-Cell Trajectory Inference

sclsd implements Latent Space Dynamics (LSD), a thermodynamic framework for modeling cell differentiation from single-cell RNA sequencing data.

Notebooks for reproducing manuscript figures and analyses are available at csglab/sclsd-manuscript.

Overview

LSD reinterprets Waddington's epigenetic landscape as an energy landscape in a learned latent cell state space. Cell differentiation is modeled as a stochastic dynamical system governed by a gradient flow down this potential surface, combined with noise representing gene expression variability.

The model jointly infers:

• Cell state: A latent representation of each cell's gene expression profile
• Differentiation state: A 2D embedding capturing developmental progression
• Waddington potential: An energy function whose gradient defines differentiation dynamics
• Developmental entropy: A measure of cellular plasticity derived from the uncertainty in differentiation state

Installation

pip install sclsd

Or from source:

git clone https://github.com/csglab/sclsd.git
cd sclsd
pip install -e .

[!NOTE] As a lightweight Python package, installation time varies depending on pre-existing dependencies in your environment, starting from scratch, expect it to take less than 10 minutes.

Dependencies

• Python ≥3.9
• PyTorch ≥2.0.0
• Pyro-PPL ≥1.8.0
• torchdiffeq ≥0.2.0
• scanpy ≥1.9.0
• cellrank ≥2.0.0

Quick Start

import scanpy as sc
import torch
from sclsd import LSD, LSDConfig

# Load preprocessed AnnData (log-normalized, with neighbors computed)
adata = sc.read("data.h5ad")

# Configure model
cfg = LSDConfig()
cfg.model.z_dim = 10           # Cell state dimensionality
cfg.walks.path_len = 50        # Trajectory length for training
cfg.walks.num_walks = 4096     # Number of training trajectories

# Initialize model
device = torch.device("cuda" if torch.cuda.is_available() else "cpu")
lsd = LSD(adata, cfg, device=device)

# Set prior transition matrix from pseudotime
lsd.set_prior_transition(prior_time_key="dpt_pseudotime")

# Generate training trajectories
lsd.prepare_walks()

# Train
lsd.train(num_epochs=100)

# Get results
result = lsd.get_adata()

Output

After training, lsd.get_adata() returns an AnnData object with:

Key	Location	Description
X_cell_state	obsm	Latent cell state representation
X_diff_state	obsm	2D differentiation state embedding
potential	obs	Waddington potential value
entropy	obs	Developmental entropy (plasticity)
lsd_pseudotime	obs	Pseudotime derived from potential
transitions	obsp	Cell-cell transition probability matrix

Key Methods

Cell Fate Prediction

Propagate cells through the learned landscape to predict terminal fates:

result = lsd.get_cell_fates(
    adata=result,
    time_range=15.0,
    cluster_key="clusters",
    return_paths=True
)
# Predicted fates stored in result.obs["fate"]

Velocity Streamlines

Visualize differentiation flow fields:

lsd.stream_lines("X_umap", color="clusters")

In Silico Gene Perturbation

Simulate gene knockouts and predict fate changes:

X = torch.from_numpy(result.X.toarray()).float()
perturbed_fates, unperturbed_fates = lsd.perturb(
    adata=result,
    x=X,
    gene_name="Noto",
    cluster_key="clusters",
    perturbation_level=0  # Knockout
)

Configuration

Key parameters in LSDConfig:

cfg = LSDConfig()

# Model architecture
cfg.model.z_dim = 10              # Cell state dimensions
cfg.model.B_dim = 2               # Differentiation state dimensions (fixed at 2)
cfg.model.V_coeff = 0.01          # Potential regularization

# Training trajectories
cfg.walks.path_len = 50           # Steps per trajectory
cfg.walks.num_walks = 4096        # Number of trajectories
cfg.walks.batch_size = 256        # Batch size

# Optimizer
cfg.optimizer.adam.lr = 1e-3      # Learning rate

Data Requirements

Input AnnData should contain:

• Log-normalized expression in adata.X
• Raw counts in adata.layers["raw"]
• Library sizes in adata.obs["librarysize"]
• Precomputed neighbor graph in adata.obsp["connectivities"]
• Pseudotime values (e.g., from diffusion pseudotime) for prior initialization

Method

LSD models cell state dynamics via the stochastic differential equation:

$$dz = -\nabla V(z) , dt + \sigma , dW$$

where $V(z)$ is the Waddington potential parameterized by a neural network, and the gradient defines a neural ODE. The model is trained by variational inference, reconstructing gene expression through a zero-inflated negative binomial likelihood.

Training trajectories are generated by random walks on a k-nearest neighbor graph, biased by pseudotime to follow developmental progression.

Citation

If you use sclsd, please cite:

Poursina A, Hajhashemi S, Mikaeili Namini A, Saberi A, Emad A, Najafabadi HS. A Latent Space Thermodynamic Model of Cell Differentiation. 2026.

License

MIT License