Hematopoiesis is the process of blood cell formation from hematopoietic stem cells (HSCs). Adult HSCs reside in a special microenvironment within the bone marrow (BM) called the HSC niche whose anatomical and functional properties are just beginning to be uncovered. The importance of the microenvironment is illustrated by the fact that HSCs taken out of their niche have yet to be successfully expanded ex vivo. While multiple cellular components and soluble factors have been shown to contribute to the establishment of the HSC niche, the central role of oxygen as a critical physiological factor governing cell function cannot be overlooked in considering the biology of the HSC in vivo. The BM is generally considered to be hypoxic (low oxygen tension), but the relationship between local oxygen distribution and the microanatomy of the HSC niche remain poorly defined, in part because of our inability to probe oxygen tension in vivo with cellular resolution. Here we propose to develop molecular imaging technology to enable high-resolution 3D visualization and quantification of local oxygen tension in the BM of live mice. We will use the technology to study if HSC homing and retention in the BM is regulated by local oxygen tension and by hypoxia-inducible factor-1 (HIF-1) dependent cellular response. We will further investigate if anaerobic metabolism is essential for HSC function in vivo. The proposed research requires close collaboration of a multidisciplinary team of investigators with diverse expertise in molecular imaging, optical technology, and stem cell biology.
Narrative Hematopoiesis is the process of blood cell formation from hematopoietic stem cells that reside in the bone marrow. We propose to examine how stem cells respond to oxygen distribution in the bone marrow.
|Wu, Juwell W; Runnels, Judith M; Lin, Charles P (2014) Intravital imaging of hematopoietic stem cells in the mouse skull. Methods Mol Biol 1185:247-65|
|Ramsey, Haley; Zhang, Qi; Brown, Diane E et al. (2014) Stress-induced hematopoietic failure in the absence of immediate early response gene X-1 (IEX-1, IER3). Haematologica 99:282-91|
|Spencer, Joel A; Ferraro, Francesca; Roussakis, Emmanuel et al. (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269-73|
|Saez, Borja; Ferraro, Francesca; Yusuf, Rushdia Z et al. (2014) Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood 124:2937-47|
|Carlson, Alicia L; Fujisaki, Joji; Wu, Juwell et al. (2013) Tracking single cells in live animals using a photoconvertible near-infrared cell membrane label. PLoS One 8:e69257|
|Kalaitzidis, Demetrios; Sykes, Stephen M; Wang, Zhu et al. (2012) mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell 11:429-39|
|Lo Celso, Cristina; Scadden, David T (2011) The haematopoietic stem cell niche at a glance. J Cell Sci 124:3529-35|
|Fujisaki, Joji; Wu, Juwell; Carlson, Alicia L et al. (2011) In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 474:216-9|
|Ferraro, Francesca; Lymperi, Stefania; Méndez-Ferrer, Simón et al. (2011) Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med 3:104ra101|
|Sykes, Stephen M; Lane, Steven W; Bullinger, Lars et al. (2011) AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146:697-708|