By September 25, 2020


Studies of intestinal homeostasis have focused largely on replacement of differentiated cells that are lost due to digestive function and exposure to ingested bacteria and chemical damage. However, mechanisms of ISC replacement have been largely unexplored. To determine if and how Drosophila ISCs are replaced after loss we developed a starvation assay to induce rapid loss of stem cells. Within two days of starvation, severe regional loss of approximately half of the total ISC population in the posterior midgut occurred. Upon re-feeding of starved animals, the ISC number returned to that of controls, demonstrating that mechanisms, currently unknown, are in place toprecisely regulate the ISC number. Studies in other systems have revealed that lost stem cells are replaced bysymmetric divisions of remaining stem cells. However, our analysis demonstrated that generation of new stem cells appeared to proceed through a spindle-independent ploidy reduction of cells in the enterocyte lineage through a process known as amitosis (Lucchetta and Ohlstein, Cell Stem Cell 2017). Amitosis was first recognized as a specialized form of cell division in chicken red bloodcells by Robert Remak in 1841 and has been identified in a vast array of species, from primitive ciliates to mammals, and is implicated in generation of some forms of cancer.

Our work establishes a new paradigm of stem cell replacement involving dedifferentiation of polyploid enterocytes to ISCs and may provide insight into the currently unknown mechanisms of ploidy reduction in tissue homeostasis and cancer. Ploidy reduction has been documented in hepatocytes and ploidy reduction of tumor cells that escape mitotic catastrophe secondary to irradiation has been shown to give rise to a mitotically active population of cells. In addition, we have determined that amitosis initiates in aging animals and upon ISC dysfunction during proliferative demand. As we now have multiple assays that induce ploidy reduction of enterocytes, we can use this model to identify pathways that regulate this enigmatic process and provide mechanistic insight into amitosis and ploidy reduction in other systems.

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