Distinct bone marrow blood vessels differentially regulate haematopoiesis

Abstract

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.

Quantification and three-dimensional microanatomical organization of the bone marrow

“…Many of the niches are constructed around diverse microvessel types, which distinctly regulate access to nutrients, oxygen, and metabolites derived from circulating blood. [64][65][66] Nevertheless, for the most part, available data on BM subcompartments remain fragmentary, and a broader picture integrating comprehensive spatial patterns and number of niches in an organ-wide context is lacking. In fact, only a limited number of studies have analyzed cell subset localization at a global scale and thus explored the hypothesis that hematopoietic cells distribute in a nonarbitrary fashion in accordance to a defined zonation of the BM landscape.…”

“…103,104 In addition, a minor fraction enriched in quiescent HSCs has been reported to localize in a protective niche adjacent to nonpermeable arterioles, under the regulatory influence of neighboring Nestin-GFP hi , NG2 1 mesenchymal cells (nes) and nonmyelinating Schwann cells (in yellow). 32,55,65 (ii) B-cell progenitors have been suggested to sequentially migrate along different niches as they progress through maturation. Early stage pre-pro B cells are mostly found adjacent to the cell bodies of CAR cells and migrate toward IL-7-expressing CAR cells as they enter the pro B cell stage.…”

Dissecting the bone marrow HSC niches

“…Actually, in adult BM, multiple niche cell populations from distinct BM zones have been reported to regulate HSCs for long-term maintenance, proliferation, and differentiation. A recent report by Itkin et al [4] provided strong evidence to support the concept that different coexisting niche compartments regulate HSCs in different states.…”

New agents in HSC mobilization

“…Similar to CXCR4 i-bodies, anti-CXCR4-and anti-SDF-1-blocking antibodies also fail to mobilize HSC [51] and support the notion that direct inhibition of CXCR4/SDF-1 chemotaxis by CXCR4 antagonists is only partially responsible for HSC mobilization and likely requires perturbation of CXCR4-dependent downstream signalling (Reviewed in [52]). Indeed, additional mechanisms for AMD3100-mediated HSC mobilization has been attributed to ROS signalling and CXCR4-dependent SDF-1 release [53] as well as AMD3100-induced reduction of BM vascular integrity and increased vascular permeability [54]. As such, complete understanding of the detailed downstream effects that are mediated by CXCR4 inhibition will aid in improving future developments of HSC mobilization agents based on CXCR4 antagonists.…”