Programmed cell death and tissue regeneration: a link that should be resolved

Cellular homeostasis is maintained by three important physiological processes: proliferation, characterized by an increase in cell number; differentiation, characterized by either an increase or a decrease in cell number coincident with changes in cellular genotype and function; and cell death, which promotes the elimination of cells. Two of these alterations, proliferation and differentiation, are tightly linked to regeneration. Currently, >10 modes of programmed cell death are recognized. Among them are apoptosis, necroptosis, pyroptosis, ferroptosis, etc. Almost all of them are linked to tissue regeneration. Dead cells have a vital effect on the living cells around them. They release a wide range of stimuli (low-molecular-weight molecules, proteins, vesicles, etc.) that signal neighbors to proliferate and differentiate. Additionally, dying cells free the space and thus change the physical characteristics of tissue, arrange the elimination of dysfunctional cells, and promote regeneration. However, programmed cell death can inhibit cell proliferation and vice versa. Thus, stem cells are resistant to the induction of death and maintain their potential to affect tissue homeostasis and recovery after injury. Disturbances in the balance between cell death and regeneration lead to various pathologies. Given the importance of the interaction between cell death and regeneration, advances in this area could lay the foundation for the successful development of a rapidly growing, groundbreaking field of medicine called regenerative biomedicine, the goal of which is to support cell renewal and restore damaged organs and tissues. Here, we review these multilevel relationships to explore how cell death and regeneration balance each other.