Nucleated Erythrocytes: Linking Structure, Mechanics, Function, and Stress Responses

Red blood cells have traditionally been studied through mature mammalian erythrocytes, which provide a model of highly deformable enucleated cells. However, nucleated erythrocytes retained by birds, fish, amphibians, and reptiles represent a distinct circulating cell strategy that integrates membrane–skeleton organization, cytoplasmic properties, nuclear structure, organelle function, and stress responses. This review uses human mature red blood cells as a mechanical reference rather than a replacement model to examine how conserved and nucleus/organelle-associated mechanisms link erythrocyte structure, mechanics, and function. Current evidence indicates that nucleated erythrocytes can be considered composite cellular systems in which the nucleus may contribute to local mechanical heterogeneity and deformation behavior, although direct causal links to whole-cell mechanical phenotypes remain insufficiently established. Comparative studies across vertebrate models reveal complementary insights into nuclear regulation, metabolic adaptation, immune responses, and stress tolerance. The major challenge is to establish causal relationships between structural remodeling, mechanical changes, and physiological outcomes using integrated mechanical, imaging, and molecular approaches. This review highlights nucleated erythrocytes as valuable models for understanding the relationships among cellular architecture, mechanics, and function beyond the conventional enucleated red blood cell paradigm.