The loss of terminally differentiated cells in organs that lack active stem cell populations underlies the morbidity of numerous diseases including diabetes, heart attack, stroke, and neurodegeneration as well as many aspects of aging. In these contexts, the differentiated cells permanently exited the cell cycle in the process of differentiation and therefore any remaining functional cells cannot replenish the lost cells. Undoubtedly, a means of making terminally differentiated cells proliferate could alleviate myriad diseases and counteract aging across organ systems.
Although proliferation and differentiation might seem mutually exclusive, the liver—and the hepatocytes responsible for the majority of its mass and function—stand out as notable and informative exceptions. In the uninjured liver, essentially all functional hepatocytes are quiescent and may remain in this non-proliferative state for months to years. However, if liver mass or function is ever compromised, these cells will immediately re-enter the cell cycle and proliferate to regenerate the organ. Although cellular quiescence and liver regeneration are long-studied phenomena, much of our understanding of quiescence is based on artificial cell culture systems and we still do not understand why the liver, but not other organs, has regenerative capacity. Using the mouse liver as a physiologic and tractable system, we are developing and employing tools to probe the molecular regulation of these processes in their native context from the level of single cells to whole organism. Our investigations will first and foremost fill critical gaps in our understanding of the quiescent state and liver regeneration and ultimately uncover new avenues for enabling regeneration across organ systems.
How does the liver balance function and proliferation?
Hepatocytes are among only a few cell types that are highly differentiated with multiple specialized functions yet still capable of proliferation. However, it is unclear if and how hepatocytes balance function and proliferation in the setting of liver regeneration. We are employing lineage tracing, transcriptomics, and functional assays in vivo to understand how hepatocytes—and the liver as a whole—balance multiple demands in order to simultaneously maintain organ function and increase cell number following liver injury.
What genes are required for the maintenance and reversibility of quiescence?
Quiescent cells, unlike terminally differentiated cells, retain the ability to re-enter the cell cycle after prolonged dormancy. However, both quiescent and terminally differentiated cells have similar expression of canonical cell cycle genes at baseline. Thus, the functional distinction between quiescence and terminal differentiation completely lacks a molecular explanation. We are developing in vivo genome-wide screening approaches to identify genes required for the maintenance and reversibility of this unique cell cycle state in the liver. The molecular features that define quiescence will provide candidates for attempts to confer proliferative capacity to terminally differentiated cells—to make a cardiomyocyte or neuron divide again.
How does an organism sense and respond to liver insufficiency?
Liver injury and impaired liver function lead to immediate and dramatic changes in circulating metabolites and proteins with consequences for all organ systems. It is unknown how an organism senses liver insufficiency in order to initiate the processes that maintain homeostasis and drive regeneration. We are employing organism-wide analyses to identify the tissues and cell types that respond to liver insufficiency, the mechanisms by which insufficiency is sensed, and the physiologic consequences of these responses such that the organism can both maintain homeostasis and initiate regeneration following liver injury.
Why can’t terminally differentiated cells divide?
Unlike hepatocytes, most differentiated cells permanently exit the cell cycle and are therefore considered to be terminally differentiated. In addition to our investigation of liver regeneration, we are employing injury models in other organ systems, such as the heart, to understand how injury in these tissues differs from injury in the liver and why the parenchymal cells in these tissues cannot re-enter the cell cycle. Through parallel studies of contexts that are both permissive and not permissive for regeneration, we will uncover key pathways through which we could ultimately confer regenerative capacity to classically non-regenerative tissues in the setting of disease.