Hematopoietic stem cells (HSC) are rare primitive cells capable of reconstituting all blood cell lineages throughout the life of an individual. My research program focuses on the microenvironment in which HSC reside, which is essential for their survival, self-renewal and differentiation. This microenvironment, or niche, has been difficult to define, but recent studies from our laboratory and others have shown that osteoblasts, the bone-forming cells, are an essential component of this complex cellular network. We established that parathyroid hormone (PTH), through activation of the PTH/PTHrP receptor (PR) in osteoblastic cells, could alter the HSC niche resulting in HSC expansion in vivo and in vitro and improving dramatically the survival of mice receiving bone marrow transplants. These findings are of great clinical appeal, because they suggest that a strategy aimed at modifying supportive cells in a stem cell niche can expand HSC. Since HSC are currently used in bone marrow transplantation and in the treatment of bone marrow failure states, these findings are clearly of great relevance to human disease.

Current research projects include:

1. Delineation of changes in molecular and cellular osteoblastic-HSC interactions which are modulated by the PR We will particularly evaluate members of the Notch/Jagged signaling pathway, which we and others showed to be important in microenvironmental-HSC interactions;

2. Definition of the role of osteoblastic activation in the PTH-dependent improved survival after myeloablation;

3. Identification of the osteoblastic cell type necessary for support of hematopoietic stem cells;

4. Analysis of PTH-dependent HSC effects in human cell systems.

The availability of PTH as a safe treatment for osteoporosis makes these studies particularly relevant to human disease. In addition, the use of PTH to mediate HSC expansion illustrates the benefit of pharmacological manipulation of the HSC niche. Since the Jagged1/Notch signaling pathway has been implicated in the microenvironmental control of stem cell self-renewal in several organ systems, definition of Jagged1 modulation, which is currently poorly understood, should provide additional molecular targets for stem cell regulation. The studies proposed are therefore designed to result in findings that not only advance the understanding of stem cell-microenvironmental interactions, but also devise pharmacologic strategies that can be brought back to patients, directly impacting their clinical care.