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Mechanogenomic Virtual Cell Wiki

Welcome to the documentation of the Mechanogenomic Virtual Cell.

This project implements a minimal physical-computational model of nuclear mechanotransduction. The model links substrate stiffness to cellular traction, nuclear stress, nuclear deformation, YAP/TAZ activity, and fibrosis-associated mechanosensitive gene trajectories.

The goal of this wiki is to document each physical module of the model separately and explain how they are integrated into a complete virtual-cell framework.

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Model overview

The mechanogenomic virtual cell follows a physical causal chain:

$$E \rightarrow T(E) \rightarrow \sigma_{nuc}(E) \rightarrow A(t),\;YAP/TAZ,\;genes$$

where:

Term	Meaning
E	Substrate or tissue stiffness
T(E)	Cell-generated traction
sigma_nuc(E)	Effective nuclear stress
A(t)	Time-dependent projected nuclear area
YAP/TAZ	Nuclear mechanotranscriptional activity
genes	Mechanosensitive gene-expression outputs

In this framework, hepatic fibrosis is modeled as a progressive increase in tissue stiffness. This allows fibrosis stages to be interpreted as points along a mechanical axis.

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Individual model pages

The full model is divided into independent but connected modules.

1. Motor-Clutch Model

Motor-Clutch Model

The motor-clutch model describes how substrate stiffness is converted into cellular traction through actomyosin contractility and integrin-based adhesions.

Main output:

$$T(E)$$

This module acts as the mechanical engine of the virtual cell.

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2. Nuclear Mechanics Model

Nuclear Mechanics Model

The nuclear mechanics model describes how cellular traction is transmitted to the nucleus and converted into nuclear stress, nuclear deformation, lamin A/C-dependent mechanical gating, and YAP/TAZ activation.

Main outputs:

$$\sigma_{nuc}(E),\quad A(t),\quad YAP_{N/C}$$

This module acts as the mechanosensitive core of the virtual cell.

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Integrated virtual-cell architecture

The complete model combines the following steps:

Step	Module	Input	Output
1	Stiffness mapping	E	kappa
2	Motor-clutch model	kappa, myosin motors, molecular clutches	T(E)
3	Force transmission	T(E), kappa, k_c	sigma_nuc(E)
4	Lamin-gated nuclear mechanics	sigma_nuc, ell	A_ss(E)
5	Nuclear dynamics	A_ss(E), tau	A(t)
6	YAP/TAZ gating	sigma_nuc, ell	YAP_N/C
7	Population mixture	E, t, phi	Nuclear-area distribution
8	Fibrosis mapping	Fibrosis stage	Mechanogenomic trajectory

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Biological interpretation

The model is based on the idea that cells sense stiffness by generating force.

In soft environments, force transmission is weak.
In stiff environments, integrin clutches load more efficiently, actomyosin-generated traction increases, and more mechanical stress reaches the nucleus.

The nucleus responds through lamin A/C-dependent mechanics. This produces changes in nuclear area, YAP/TAZ nuclear localization, and mechanosensitive gene expression.

In hepatic fibrosis, tissue stiffening may therefore act as a physical driver of mechanogenomic remodeling.

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Fibrosis stiffness axis

Approximate stiffness values used in the model:

Fibrosis stage	Approximate stiffness
F0	~4 kPa
F1	~7 kPa
F2	~9.5 kPa
F3	~13 kPa
F4	~23-26 kPa

The model uses this mechanical axis to predict how nuclear mechanotransduction changes during fibrosis progression.

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Experimental connection

The model is calibrated and validated using:

• primary hepatocytes cultured on soft and stiff hydrogels;
• confocal microscopy of nuclear morphology;
• nuclear-area distributions over time;
• fibrosis-associated RNA-seq trajectories;
• planned qPCR validation under fibrosis-like stiffness conditions.

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Core outputs

The main predicted outputs are:

Output	Description
T(E)	Cell-generated traction
sigma_nuc(E)	Nuclear stress
A_ss(E)	Steady-state nuclear area
A(t)	Time-dependent nuclear area
YAP_N/C	YAP nuclear-to-cytoplasmic ratio
P(A|E,t)	Nuclear-area population distribution
Mechanosensitive genes	Predicted fibrosis-associated gene activation

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Mechanosensitive gene modules

Representative gene groups include:

Module	Example genes
YAP/TAZ-TEAD signaling	YAP1, WWTR1, TEAD2, TEAD4, CCN2
Nuclear envelope and lamina	LMNA, LMNB2, NUP93, TPR, TMPO
Adhesion and cytoskeleton	VCL, ILK, SRC, MYH9, MYL9, FLNA, CFL1
Matrix remodeling and fibrosis	LOX, COL1A1, COL1A2, VIM, ACTA2

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Recommended wiki structure

Home
Motor-Clutch-Model
Nuclear-Mechanics-Model
Fibrosis-Stiffness-Mapping
Gene-Trajectories
Experimental-Validation
Model-Parameters

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Current status

This repository currently contains the computational core of the mechanogenomic virtual-cell model.

The model is being developed to integrate:

1. physical modeling of cell-substrate mechanosensing;
2. nuclear mechanics and lamin A/C-dependent deformation;
3. YAP/TAZ mechanotranscriptional activation;
4. fibrosis-associated gene-expression trajectories;
5. experimental validation in hepatocytes cultured on hydrogels.

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Suggested citation

If you use this model or repository, please cite:

Mechanogenomic Virtual Cell: a physical-computational model of nuclear mechanotransduction

Author: Daniel Pérez-Calixto
Repository: https://github.com/Danpc11/mechanogenomic-virtual-cell

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Quick navigation

• Motor-Clutch Model
• Nuclear Mechanics Model
• Fibrosis Stiffness Mapping
• Gene Trajectories
• Experimental Validation
• Model Parameters