Proliferation maintains the undifferentiated status of stem cells: The role of the planarian cell cycle regulator Cdh1

Stem cells like fertilized eggs, embryonic stem cells (ESCs), hematopoietic stem cells, myoblasts and fibroblasts, are capable of self-renewal and differentiation. The balance between differentiation and proliferation is required for development, homeostatic tissue turnover and regeneration. Differentiation is regulated by “induction signals” and “competence”. Previous research work suggest that the cell cycle and differentiation are correlated, though the exact relationship is still unknown. Some studies also suggest that CDK (Cyclin-dependent kinase) activity is important for the progression of cell cycle, but due to the activity of ubiquitin E3-ligase, APC/C-Cdh1, cyclins get degraded, and cyclin levels becomes lowest in early G-1 phase. Hence Cdh1 inactivation could be helpful in cell cycle progression. One major hurdle why such correlation studies between cell cycle and differentiation were not possible before is the complexity and dynamic conversion of the cell cycle state which occurs several times in the course of development.

Planarians are organisms that can regenerate missing body part from a tiny body fragment. Adult stem cells termed “neoblasts” are responsible for their amazing regeneration abilities. Planarians lack 124 genes that are important for mice or humans according to a genome scan of various planarians species.

In a new study published in Developmental Biology by Professor Chikara Hashimoto and colleagues from JT Biohistory Research Hall found that planarians lack CDK inhibitor genes in D. japonica but exist Cdh1 genes which are responsible for cell cycle exit. The authors found that proliferative stem cells were unable to respond to induction signals, and Cdh1 expression and cell cycle exit were required for differentiation to begin. Cyclin D knockdown (cyclin D KD) planarians which are assumed to be driven to quit the cell cycle were unable to regenerate their missing body parts and lost their neoblasts.

The cell cycle must be maintained for stem cells to exist in tissues without differentiation. The incompatibility of proliferation and differentiation in the regulation of transcription factors and chromatin state was also discussed in their study. For example, in mouse ESCs, the cyclin D-CDK and cyclin E-CDK complexes phosphorylate oct4, sox2, and nanog to protect them from proteasomal destruction, implying that cell cycle progression keeps stem cells alive.

The research team reported that planarians have a very simple cell cycle regulatory mechanism, where Cdh1 is the key components in cell cycle exit. Cdh1 KD disrupting cell cycle exit resulted in a dramatic increase in neoblasts and a decrease in differentiated cells. Additionally, even in the presence of induction signal, the Cdh1-depleted neoblasts did not differentiate. These findings suggested that cell cycle exit is required for stem cell differentiation. In other word, cell cycle progression guarantees that stem cells remain undifferentiated. The occurrence of two distinct growth pauses, i.e. G1 arrest and G0 is suggested by researchers. Cells in G1 arrest, like neural crest cells and quiescent adult stem cells, stop their cell cycle but stay in G1 to retain their undifferentiated status. Cells in G0, on the other hand, complete their cell cycle and gain the ability to respond to induction signals.

According to the authors, the new study suggests that causal relationship between proliferation and differentiation could be conserved among multicellular organisms: Proliferation maintains the undifferentiated status and cell cycle exit to G0 dictates cells to become competent to accept induction signals.