Stem Cell Rejuvenation

Effective functioning of the body’s tissues and organs depends upon innate regenerative processes that maintain proper cell numbers during homeostasis and replace damaged cells after injury. In many tissues, regenerative potential is determined by the presence and functionality of dedicated populations of stem and progenitor cells, which respond to exogenous cues to produce replacement cells when needed. Understanding how these unspecialized precursors are maintained and regulated is essential for understanding the fundamental biology of tissues. In addition, this knowledge has practical implications, as stem cell regenerative potential can be exploited therapeutically by transplantation to replenish the stem cell pool or by pharmacological manipulation to boost the repair activity of cells already present in the tissue. Ongoing work in my laboratory focuses on defining how changes in stem cell activity impact tissue regeneration throughout life, and identifying physiological and pathological signals that modulate regenerative function in an age-dependent manner. Our recent data using parabiosis and transplantation models suggests that the circulatory system serves as a major source of such signals. In particular, exposure of aged tissues, including skeletal muscle, cardiac muscle and neural cells, to a “youthful” systemic environment appears to reverse many indicators of age-related pathology and restores robust regeneration following injury. While prior studies have identified a handful of systemic “aging” factors, discovery of the humoral “rejuvenating” factors that act on tissue stem cells to restore regenerative function has been relatively more elusive. In recent work, we identified that the circulating hormone Growth Differentiation Factor 11 (GDF11) is a rejuvenating factor for skeletal muscle and other tissues. Supplementation of systemic GDF11 levels, which normally decline with age in mice and humans, was sufficient to restore stem cell function in the skeletal muscle and other tissues, and improved physical function in aged mice. Taken together, these data reveal critical mechanisms in the regulation of aging by blood-borne factors and identify a promising therapeutic target candidate for the reversal of age-related tissue and stem cell dysfunction.