Evolution of hierarchy and irreversibility in theoretical cell differentiation model

• Published in: PNAS nexus 2024-01, Vol.3 (1), p.pgad454-pgad454
• Main Authors: Nakamura, Yoshiyuki T, Himeoka, Yusuke, Saito, Nen, Furusawa, Chikara
• Format: Article
• Language: English
• Subjects: Analysis; Biological, Health, and Medical Sciences; Cell differentiation; Genes; Mathematical models
• ISSN: 2752-6542; 2752-6542
• DOI: 10.1093/pnasnexus/pgad454

Abstract The process of cell differentiation in multicellular organisms is characterized by hierarchy and irreversibility in many cases. However, the conditions and selection pressures that give rise to these characteristics remain poorly understood. By using a mathematical model, here we show that the network of differentiation potency (differentiation diagram) becomes necessarily hierarchical and irreversible by increasing the number of terminally differentiated states under certain conditions. The mechanisms generating these characteristics are clarified using geometry in the cell state space. The results demonstrate that the hierarchical organization and irreversibility can manifest independently of direct selection pressures associated with these characteristics, instead they appear to evolve as byproducts of selective forces favoring a diversity of differentiated cell types. The study also provides a new perspective on the structure of gene regulatory networks that produce hierarchical and irreversible differentiation diagrams. These results indicate some constraints on cell differentiation, which are expected to provide a starting point for theoretical discussion of the implicit limits and directions of evolution in multicellular organisms.