Distinct Bone Marrow Blood Vessels Differentially Regulate Normal and Malignant Hematopoiesis - ICMS2015 Abstract Submission Form Tumor Microenvironment Conference

Tomer Itkin ¹ Shiri Gur Cohen ¹ Joel Spencer ² Amir Schajnovitz ² Saravana Ramasamy ³ Anjali Kusumbe ³ Guy Ledergor ¹ Yookyung Jung ² Idan Milo ¹ Michael Poulos ⁴ Alexander Kalinkovich ¹ Aya Ludin ¹ Orit Kollet ¹ Guy Shakhar ¹ Jason Butler ⁴ Shahin Rafii ⁴ Ralf Adams ³ David Scadden ² Charles Lin ² Tsvee Lapidot ¹

¹Department of Immunology, Weizmann Institute of Science
²Department of Stem Cell and Regenerative Biology, Harvard Medical School
³Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine
⁴Department of Genetic Medicine, Weill Cornell Medical College

Bone marrow (BM) endothelial cells (BMECs) form a network of blood vessels (BVs) that regulate both leukocyte trafficking and hematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how do BMECs balance between these dual regulatory roles and if these events occur at the same vascular sites. BM arteries were found to be mostly encircled by αSMA⁺ pericytes whereas the ensuing small-diameter endosteal arterioles were mostly surrounded by stem cell-niche supporting stromal precursor cells. These endosteal arteriole BVs exhibited reduced permeability and high levels of adhesion- and tight-junction molecules. Primitive HSPCs located in peri-arteriole regions were found in a non-activated, low reactive oxygen species (ROS) state. Live imaging studies revealed that immature and mature leukocyte trafficking occurred exclusively through the more permeable sinusoids, located downstream to the endosteal arterioles. The BM sinusoids also contain a higher prevalence of ROS^high cells in their microenvironment. In line with these results we show that during conditions favoring BM HSPC expansion, endothelial integrity is enhanced along with reduced HSPC bi-directional trafficking. Conversely, disruption of endothelial barrier augmented ROS levels in HSPC, enhancing their bi-directional trafficking while reducing their BM maintenance. In the context of malignancy, engrafted human pre-B ALL cells facilitated enhanced endothelial barrier integrity and reduced BM permeability. Clinical studies reported that pre-B ALL patients exhibit higher levels of angiogenic factors alongside with increased prevalence of BM BVs density (Perez-Atayde et al., Am J Pathol. 1997). Moreover, pre-B ALL cells occupy and modify the vascular niche on the expense of normal HSPC (Colmone et al., Science 2008). Taken together, we suggest that malignant cells modify the endothelial barrier to facilitate a protective and leukemia-supportive microenvironment.