We seek to understand how tissues sense and respond to damage with the long-term goal of developing novel approaches for regenerative medicine. We focus on the mammalian liver, which has the unique ability to completely regenerate itself after injury, in order to identify the molecular requirements for regeneration and ultimately confer this capacity to non-regenerative tissues. To this end, we develop and employ novel genetic, molecular, and cellular tools that allow us to dissect and modulate organ injury and repair directly in the organism.
The damage or death 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 enabling terminally differentiated cells to renew and 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 an organism sense and respond to organ injury?
Organ damage disrupts both local and systemic homeostasis and the body responds with some combination of inflammation, fibrosis, or repair. In the case of the liver, it is unknown how the organism senses liver injury and initiates regeneration. We are employing organism-wide approaches 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. By understanding how an organism responds to injury with regeneration, we bring ourselves closer to the ability to modulate injury responses in presently non-regenerative tissues such that injury is met with regeneration rather than fibrosis.
How does the liver balance function and regeneration?
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 and whether all hepatocytes have equivalent proliferative capacity. 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 restore organ mass.
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 that regulate proliferative capacity in quiescent and terminally differentiated cell types. The molecular features will provide candidates for attempts to confer proliferative capacity to terminally differentiated cells—to make a cardiomyocyte or neuron divide again.