Direct visualization and characterization of hypoxia in the bone marrow

描述（由申请人提供）：造血是由造血干细胞（hsc）形成血细胞的过程。成人造血干细胞存在于骨髓（BM）内一个特殊的微环境中，称为造血干细胞生态位，其解剖学和功能特性刚刚开始被发现。微环境的重要性体现在造血干细胞脱离其生态位尚未成功地在体外扩展这一事实。虽然多种细胞成分和可溶性因子已被证明有助于HSC生态位的建立，但在考虑体内HSC的生物学时，氧作为控制细胞功能的关键生理因素的核心作用不容忽视。BM通常被认为是缺氧的（低氧张力），但局部氧分布与HSC生态位显微解剖之间的关系仍然不明确，部分原因是我们无法用细胞分辨率探测体内的氧张力。在此，我们建议开发分子成像技术，以实现活体小鼠脑脊膜局部氧张力的高分辨率3D可视化和定量。我们将使用该技术来研究HSC在脑脊膜中的归巢和保留是否受局部氧张力和缺氧诱导因子-1 （HIF-1）依赖性细胞反应的调节。我们将进一步研究无氧代谢是否对体内HSC功能至关重要。拟议的研究需要在分子成像、光学技术和干细胞生物学方面具有不同专业知识的多学科研究小组的密切合作。

DESCRIPTION (provided by applicant): 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.