Laboratory of Genetics
Emerald Foundation Developmental Chair
Stem cells are the building blocks during development of organisms as varied as plants and humans. In addition, stem cells provide for the maintenance and regeneration of tissues, such as blood and skin, throughout the lifetime of an individual. The ability of stem cells to contribute to these processes depends on their ability to divide and generate both new stem cells (self-renewal) as well as specialized cell types (differentiation). Stem cells lose the potential for continued self-renewal when removed from their normal cellular environment, known as the stem cell "niche," suggesting an essential role for the niche in controlling stem cell behavior.
The Jones lab is using fruit fly Drosophila melanogaster as a model system to establish paradigms for how stem cell behavior is controlled. Adult stem cells can be easily located in the fly intestine and testis, and the stem cells that maintain these tissues are remarkably similar to their mammalian counterparts. Therefore, it is possible to study these cells in the context of their normal environment without destroying the tissue. Being able to study the behavior of stem cells in vivo allows us to begin to ask questions about how the niche can control stem cell self-renewal and survival and how the relationship between stem cells and the niche evolves during development, as a consequence of aging, and during tumor initiation and progression. Importantly, lessons learned from the study of stem cells in fruit flies has already told us much about how stem cell behavior is regulated in more complex tissues in mammals.
Age-related changes to stem cells and the stem cell niche
Loss of tissue and organ function is a characteristic of aging, and such changes have been attributed to decreases in stem cell function. Given the relationship between reduced stem cell activity, loss of tissue homeostasis, and aging, several key questions emerge. Is loss of tissue homeostasis due to 1) a decrease in stem cell number 2) an inability of stem cells to respond to appropriately to signals from the niche 3) reduced signaling from the niche to specify stem cell self-renewal and maintenance or 4) reduced progenitor cell function? If all of these factors contribute to loss of tissue homeostasis, is any one more prevalent than the others, and which changes could be most easily targeted in the treatment of aging-related diseases? Lastly, can loss of tissue homeostasis be uncoupled from the aging process and studied independently with respect to changes in stem cell function?
Data from our lab suggest that aging of the stem cell niche is a major factor in decreased stem cell activity and tissue homeostasis over time. Therefore, we predict that when considering transplantation of stem cells, it may be necessary to transplant niche cells, in addition to stem cells, to provide a "younger" niche that may be more capable of sustaining stem cell self-renewal. Furthermore, as one of the primary risk factors for the development of cancer is increased age, these studies will reveal the consequences of aging on the regulation of tissue stem cell behavior and may highlight some of the factors that lead to the transformation of normal stem cells into cancer stem cells over time.
Stem cells, with their defining characteristics–extensive proliferative potential and an ability to give rise to one or more specialized cell types–are common in early embryos. But by adulthood, only a few stem cells remain, tucked away in their own private niches. They have, nonetheless, retained a remarkable capability: They can operate at a "steady state" to maintain and repair tissues with no apparent limit throughout life.
In the Drosophila testis, the stem cell "ecosystem" Jones studies, the stem cells sit at the tip of the testis, cradled in their niche, which is also known as the apical hub. As a stem cell divides, one daughter cell moves out of the niche to generate mature sperm cells. The remaining daughter cell stays put and retains its stem cell identity. In an earlier study, Jones and her team had shown that the hub cells send out a local signal, which supports neighboring stem cells, making hub cells an essential component of the stem cell niche.
More recently, they explored how stem cells respond to bodywide circulating signals in addition to local signals emanating from the stem cell niche. The insulin/IGF pathway, which is best known for controlling blood glucose, serves as a "nutrient sensor" and plays an important role in aging in many organisms, including fruit flies. When the researchers fed their flies a "poor," proteinless diet, the levels of circulating insulinlike peptides plummeted, and stem cell numbers started to decline. Upon re-feeding, insulin-like peptide expression and stem cell numbers recovered quickly. The study revealed that stem cells can sense changes in available nutrients and respond by maintaining only a small pool of active stem cells for tissue maintenance. When favorable conditions return, stem cell numbers multiply to accommodate increased demands on the tissue.
Elucidating the mechanisms by which the insulin/IGF pathway influences stem cell behavior under normal conditions and in response to stress has provided important insights into the use of stem cells in regenerative medicine, during wound repair, and in individuals experiencing metabolic stress.