Distinct bone marrow blood vessels differentially regulate haematopoiesis

• Published in: Nature (London) Vol. 532; no. 7599; pp. 323 - 328
• Main Authors: Itkin, Tomer, Gur-Cohen, Shiri, Spencer, Joel A., Schajnovitz, Amir, Ramasamy, Saravana K., Kusumbe, Anjali P., Ledergor, Guy, Jung, Yookyung, Milo, Idan, Poulos, Michael G., Kalinkovich, Alexander, Ludin, Aya, Golan, Karin, Khatib, Eman, Kumari, Anju, Kollet, Orit, Shakhar, Guy, Butler, Jason M., Rafii, Shahin, Adams, Ralf H., Scadden, David T., Lin, Charles P., Lapidot, Tsvee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.04.2016; Nature Publishing Group
• Subjects: 631/532/1542; 631/532/2139; Animals; Antigens, Ly - metabolism; Arteries - cytology; Arteries - physiology; Blood Vessels - cytology; Blood Vessels - physiology; Bone marrow; Bone Marrow - blood supply; Bone Marrow Cells - cytology; Calcification; Cell Differentiation; Cell growth; Cell Movement; Cell Self Renewal; Cell Survival; Chemokine CXCL12 - metabolism; Endothelial Cells - physiology; Endothelium; Female; Growth; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Homeostasis; Humanities and Social Sciences; Leukocytes - cytology; Male; Membrane Proteins - metabolism; Metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Nestin - metabolism; Pericytes - physiology; Permeability; Physiological aspects; Physiological research; Plasma - metabolism; Reactive Oxygen Species - metabolism; Receptors, CXCR4 - metabolism; Repopulation; Science; Stem cell research; Stem cells; Veins & arteries; Israel
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature17624

Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols. Bone marrow endothelial cells have dual roles in the regulation of haematopoietic stem cell maintenance and in the trafficking of blood cells between the bone marrow and the blood circulatory system; this study shows that these different functions are regulated by distinct types of endothelial blood vessels with different permeability properties, affecting the metabolic state of their neighbouring stem cells. Bone marrow blood vessel specialization Endothelial cells of the bone marrow modulate both haematopoietic stem cell (HSC) maintenance and the trafficking of blood cells out of the bone marrow. Tsvee Lapidot and colleagues find that these two aspects are controlled by two distinct types of blood vessels in the bone marrow, with different permeability properties and reactive oxygen species (ROS) levels. Less permeable arteries surrounded by pericytes maintain HSCs in a low reactive oxygen species (ROS) state, whereas the more permeable smaller sinusoids promote HSC activation and allow trafficking of immature and mature leukocytes. The authors also show that in conditions that allow for expansion of HSCs, endothelial integrity is increased, with fewer blood cells moving in and out. Disruption of the endothelial barrier has the reverse effects. Elsewhere in this issue ( page 380 ), Anjali Kusumbe et al . demonstrate that Notch signalling in endothelial cells of bone marrow induces change in the capillaries and mesenchymal stem cells of the environment to support HSC amplification.