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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097748-04
Application #
8309144
Study Section
Special Emphasis Panel (ZHL1-CSR-W (M1))
Program Officer
Thomas, John
Project Start
2009-08-24
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$564,147
Indirect Cost
$205,973
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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