UC Merced

In long-lived organisms like humans, stem cells (SCs) constantly divide to replace aged and damaged cells. Deregulation of this process leads towards aging and pathologies such as cancer and degenerative diseases. The mechanisms regulating this cellular turnover are poorly understood, mainly due to the difficulty in analyzing SCs in their natural environment. Here, we use a new approach and model organism, the planarian flatworm to study the process of SC regulation in the complexity of the whole organism. In particular, we analyze the role of signaling pathways that regulate SC response to tissue turnover and regeneration in the adult body. One such signaling pathway of interest involves the protein kinase AKT. This master regulator of cellular functions (cell survival, cell growth, protein synthesis, etc.) has been implicated in the systemic regulation SCs and disruption of this pathway has shown to be highly involved in human cancer. We have designed an effective strategy to downregulate AKT function with RNA-interference and have followed SC response during cellular turnover and tissue regeneration. This approach revealed that loss of AKT disrupts the systemic balance between SC proliferation and cell death during tissue renewal. Altogether, our results suggest a central role for AKT in regulating cell behavior during tissue renewal and repair. Our long-term goals seek to specifically use signaling pathways to control cellular behavior in vivo to customize tissue repair for therapeutic intervention in cancer and aging.