Cellular and Molecular Mechanisms of Microenvironmental Regulation of Hematopoietic Stem Cells in the Bone Marrow
To survive throughout the life of an individual, hematopoietic stem cells (or HSC), which continuously give rise to all cellular blood components, must strictly regulate their behavioral choices. These choices include self-renewal, differentiation, quiescence or death. This essential regulation of stem cells is thought to be determined at least in part by the environment, or niche, in which these cells reside. The bone forming cells, osteoblasts, have been known to support and expand HSC in vitro and co-transplantation of osteoblasts with HSC can increase engraftment rate. Work in our laboratory and others first identified osteoblastic cells as a regulatory component in the HSC niche through genetic means. A number of molecules have since been implicated in HSC-osteoblastic interaction. In fact, it has recently become evident that osteoblasts can both stimulate and limit HSC expansion, promote quiescence, coordinate HSC mobilization and, when destroyed or mutated, initiate hematopoietic dysfunction. Therefore, increasing evidence points to osteoblasts as key regulators of HSC behavior. While the HSC niche is still poorly understood, we and others have begun to demonstrate the therapeutic potential of its manipulation in animal models. Our laboratory has demonstrated that osteoblastic activation by Parathyroid Hormone (PTH) expands HSC, and improves recovery from myeloablation. Thus, the central hypothesis pursued by my laboratory is that osteoblastic cells play a central role in orchestrating microenvironmental control of the behavior of both benign and malignant HSC, and that they can be targeted for therapeutic benefit. My laboratory therefore uniquely uses techniques that bridge bone and stem cell biology to discover the regulatory components of the bone marrow microenvironment, with the long term goal of identifying targets for therapeutic manipulation.
Current areas of research include:
1) Molecular mechanisms of osteoblastic regulation of hematopoietic stem cells,
2) Role of osteoblasts in coordinating the actions of other bone marrow cellular components (osteoclasts, endothelial cells and adipocytes) for HSC regulation,
3) Regulation of malignant stem cells by bone microenvironmental factors,
4) Role of HSC niche components in response to toxic or irradiation injury,
5) Therapeutic targeting of the HSC niche to improve HSC expansion (in vivo and in vitro), response to toxic injury and malignant stem cell eradication.
Individuals working in the laboratory can expect to learn flow cytometric analysis, pharmacologic and immunohistochemical methods for studying microenvironmental interactions in several animal and in vitro models, and the necessary computational techniques for analyzing these data.
We are currently accepting applications for graduate students and post-doctoral fellow positions in Calvi Lab at the University of Rochester Medical Center. Individuals interested in conducting research on the physiology and stem cell biology within the bone marrow microenvironment are encouraged to apply. Interested candidates, please e-mail your CV and a cover letter detailing your scientific background and skills to Dr. Calvi (firstname.lastname@example.org )