Cell cycle, fate, stem cells, and the planarian schmidtea mediterranea

The replacement of differentiated cells is a major challenge for all multicellular organisms throughout their life spans. Humans, for example, must replace an estimated 10 billion cells every day, while some animals replace body parts as a result of continuous tissue homeostasis. Such turnover and body part replacement can be regulated through the maintenance, proliferation, and differentiation of somatic stem cells. Although it is clear that the fate decision of somatic stem cells to proliferate or differentiate is tightly controlled by regulating the cell cycle machinery, little is known about the cell cycle of somatic stem cells due to difficult experimental accessibility. We used an excellent in vivo model system, the planarian Schmidtea mediterranea to study the cell cycle of somatic stem cells. S. mediterranea has a relatively large population of stem cells distributed through the entire body except the area in front of photoreceptors and the pharynx. First of all, we developed and optimized methods to characterize the cell cycle of planarian stem cells using flow cytometry and fluorescentactivated cell sorting. Using these methods, we described the cell cycle of planarian total cells or specific populations. Second, for an in-depth understanding of the planarian cell cycle, we identified and characterized planarian homologs of the regulatory molecules controlling the cell cycle in other organisms. Among these molecules, we are highly interested in Smed-cdc73 due to the strong phenotype caused by RNAi and lack of functional studies of Cdc73 in stem cells. Finally, we therefore characterized the function of Smed-cdc73 in the decision for proliferation or differentiation of planarian stem cells using RNAi and molecular markers for stem cells and differentiated progeny of stem cells. We observed that stem cell proliferation was prevented, while differentiation of stem cells was accelerated in the absence of Smed-cdc73, suggesting that Smed-cdc73 is required for self-renewal of planarian stem cells. Taken together, our studies demonstrate the ability to analyze cell cycle of planarian stem cells in vivo and to identify cell cycle regulators required for stem cell functions. Studies on the cell cycle of planarian stem cells will allow valuable basic understanding of stem cell biology.