Tannishtha Reya's Lab - Research Summary

Research Summary

All the cells of the blood are derived from the hematopoietic stem cell. This cell has the remarkable ability to self-renew as well as to differentiate into mature blood cells of all lineages. The primary goal of our lab is to elucidate the signaling pathways that regulate the choice between stem cell renewal and commitment. These studies have implications not only for understanding the basic mechanisms that regulate stem cell development and oncogenic renewal, but also for enhancing stem cell based therapies for human disease.

Wnt signaling and stem cell development
We have focused in part on the Wnt signaling pathway, which is a critical regulator of normal growth and development, and a major target of mutation in human cancer. Our research shows that activation of Wnt signaling can promote stem cell self-renewal in vitro, and that this pathway is required for stem cell proliferation in vitro and reconstitution in vivo. Currently, we are using a combination of cellular, molecular and transgenic approaches to determine the role of Wnt signaling in stem cell self-renewal in vivo and to characterize the molecular mechanisms through which Wnt exerts its effect on stem cells. Moreover, since uncontrolled self-renewal is a hallmark of oncogenesis, we are also testing whether dysregulation of the Wnt pathway can contribute to hematopoietic tumors.

Signal integration at the stem cell niche
It is likely that stem cells receive multiple signals derived from the bone marrow microenvironment or the stem cell 'niche'. However little is known about how these signals relate to each other and how they are integrated by the HSCs. To begin to elucidate the relationship between extracellular signals known to influence HSC self-renewal and maintenance, we have carried out studies focusing on the relationship between Notch and Wnt signaling in HSCs. These studies have shown that the Wnt pathway is dependent on Notch signaling for maintaining an undifferentiated state but not for inducing proliferation or survival. This suggests that Wnt signaling may have a dominant effect on survival and growth, while Notch may act as a switch between self-renewal and commitment. Our current work is focused on further understanding this relationship at a molecular level and also defining the mechanisms that regulate the activation of each of these signals.

Regeneration and Repair of the Hematopoietic System
Besides renewing at a basal rate to replenish the hematopoietic compartment during homeostatic conditions, HSCs also have the capacity to rapidly regenerate and repair the hematopoietic system after damage. However little is known about the signals that regulate regeneration. To study this, we are using a system in which treatment with the chemotherapeutic drug cyclophosphamide and the growth factor G-CSF causes loss of proliferating progenitors in the bone marrow, followed by rapid expansion of HSCs to regenerate the progenitor pool. Using this model we have begun to define the microenvironmental changes that occur after damage and are sensed by HSCs to initiate the renewal process. Additionally, we are also investigating the intrinsic genetic program activated within HSCs that allows regeneration to occur.