Cell population modelling describes intrinsic heterogeneity: a case study for hematopoietic stem cells

Area of Science:

• Biotechnology
• Stem Cell Biology
• Mathematical Modeling

Background:

• Controlling stem cell properties during in vitro expansion is critical for clinical applications.
• Phenotypic heterogeneity is a key factor influencing therapeutic response, as per FDA guidelines.
• Understanding the sources of stem cell heterogeneity is essential for safe clinical use.

Purpose of the Study:

• To theoretically describe intrinsic cell population heterogeneity in a homogeneous in vitro environment.
• To investigate the factors contributing to stem cell heterogeneity during expansion.
• To provide a theoretical framework for managing stem cell heterogeneity.

Main Methods:

• Development of a bivariate population balance model.
• Coupling the model with a ligand conservation equation.
• Application of the model to hematopoietic stem cell expansion using the c-Kit/stem cell factor system.

Main Results:

• Intrinsic heterogeneity depends on ligand concentration and administration kinetics.
• The model highlights intra- and inter-generational contributions to heterogeneity.
• Dimensionless analysis shows heterogeneity is linked to cell division and steady-state attainment times.

Conclusions:

• Intrinsic stem cell heterogeneity arises even in ideal culture conditions.
• Ligand dynamics and cell division rates significantly influence heterogeneity.
• This theoretical model aids in understanding and potentially controlling stem cell heterogeneity for therapeutic purposes.