Constructive sleeper cells in regeneration: Deconstructing the quiescent state

Like covert operatives, adult stem cells lie dormant in the tissues of adult mammals, and have the ability to rapidly activate in response to environmental signals. Their mission however, is not destructive but constructive: to repair and regenerate damaged tissue, and leave behind copies of themselves for future unpredictable bouts of damage-control.

While the cells of the early embryo proliferate rapidly, self-assembling to shape the growing organism, most cells in the adult mammalian body have ceased dividing and acquire functions that are characteristic of each tissue. For example, in skeletal muscle, the contractile fibers responsible for movement, express a muscle-specific genetic program to produce and assemble regular, repeating arrays of contractile proteins that respond to nerve impulses. Associated with these muscle fibers are rare resident stem cells that temporarily idle in a resting state called quiescence. By reversing the arrested cell division program these dormant progenitor cells can make new cells, coping with routine wear and tear as well as episodes of injury. A fundamental unanswered question concerns how proliferating cells choose between two non-dividing fates: differentiating into tissue specific cells or resting as quiescent stem cells. The consequences of this choice are critical to regenerative biology, cancer and degenerative disease.

The major interest of the lab is to understand 1) The mechanisms by which reversible quiescence is activated and maintained and 2) How these dormant cells preserve the ability to return to cell division and generate the right type of differentiated cell, as well as copies of themselves.

Our approach has been to use genome-wide strategies coupled with functional analysis. Using a cultured myoblast system that models muscle stem cells, we have uncovered active controls at multiple levels of gene regulation specific to quiescence. Our studies so far indicate that quiescent cells preserve two antagonistic programs (division vs. differentiation) in an inactive but primed state. In collaborative studies with Rakesh Mishra at CCMB and Richard Harvey at VCCRI, Sydney, we are studying the epigenetic control of quiescence in adult cardiac progenitors. In addressing the role of environmental cues, we are focusing on both soluble and mechanical signals that influence quiescence in mesenchymal stem cells.

Overall, the picture that is emerging suggests that far from the passive inactive state indicated by prolonged periods of “dormancy”, quiescent cells have an actively regulated program that integrates metabolic, genetic and epigenetic controls to respond to the demands of regeneration, while suppressing uncontrolled proliferation and precocious differentiation.