Insights Into Bone Marrow Niche Stability: An Adhesion and Metabolism Route

Abstract

The bone marrow microenvironment provides critical cues for hematopoietic stem cell (HSC) self-renewal and differentiation and contributes to their malignant conversion. The microenvironment comprises a complex mixture of multiple cell types, soluble factors, and extracellular matrix in specialized regions termed 'niches.' Positioning of the various cellular players within these niches depends on their repertoire of adhesion molecules and chemotactic signaling, involving integrins and chemokine receptors and the corresponding intracellular players such as kinases and GTPases. The mechanical role of adhesion is to control the strength and morphology of the cell-cell and cell-extracellular matrix contacts and thereby the energy needed for the optimal localization of cells to their surroundings. While it is clear that biomechanical adhesive bonds are energetically expensive, the crosstalk between cell adhesion and metabolic pathways in the normal and malignant microenvironment is far from understood. The metabolic profile of the various cell types within the niche includes key molecules such as AMPK, glucose, mTOR, and HIF-1α. Here, we describe our most recent understanding of how the interplay between adhesion and these metabolic components is indispensable for bone marrow niche stability. In parallel, we compare the altered crosstalk of different cell types within the bone marrow niches in hematological malignancies and propose potential therapeutic associations.

Keywords: AML; Bone marrow; VLA-4; adhesion; integrin; metabolism; microenvironment; α4β1.

FIGURE 1

Cell-cell interactions within the BM microenvironment are shaped by adhesion and metabolism. (A) HSC/HSPC/LSC express adhesion receptors such as α4β1, CD44, and CXCR4. These receptors interact with their specific ligands such as VCAM-1, HA, and CXCL12 on non-hematopoietic cells such as stromal cells, MSCs and osteoblasts and contribute HSC quiescence. (B) The vascular niche made up of sinusoids contains numerous ECs. These ECs express large amounts of E-selectin and VCAM-1 and promote HSC/HSPC/LSC self-renewal. (C) Enhanced CXCR4-CD44 cooperativity can promote leukemic cell survival via mTOR and elevates glycolytic influx. Metabolic stress further increases AMPK activity promoting glycolysis and Hif-1α expression. High amounts of Hif-1α create a hypoxic environment followed by release of ROS. Abbreviations: HSC/HSPC, hematopoietic stem cell/hematopoietic stem and progenitor cell; LSC, leukemic stem cell; MSC, mesenchymal stem cell; EC, endothelial cell; VCAM-1, vascular cell-adhesion molecule-1; HA, hyaluronic acid; CXCL12, C-X-C Motif Chemokine Ligand 12; PSGL-1, P-selectin glycoprotein ligand-1; CXCR4, CXC receptor 4; mTOR, mammalian target of rapamycin complex; AMPK, adenosine-5′-monophosphate-activated protein kinase; Hif-1α, hypoxia-inducible factor α; ROS, reactive oxygen species.

FIGURE 2

Leukemic cell survival can be augmented by adhesion and metabolic components. AML cells express high amounts of CD44, CXCR4, and α4β1. Ligands such as HA, CXCL12, and VCAM-1 secreted by stromal cells activate the receptors and render chemoresistance. CD44-mediated activation and clustering of α4β1 leads to adhesive hubs and promotes mTOR activity. CXCL12 interaction with CXCR4 can be followed by enhanced glycolysis. CXCR4 interaction with CD44 confers a cancer stem cell phenotype via Oct4, Sox2, and Nanog expression. Elevated CD44 expression increases ROS levels via NADPH oxidase and further promotes malignancy. Abbreviations: FAK, focal adhesion kinase.