Hematopoietic progenitor cells regulate their niche microenvironment through a novel mechanism of cell-cell communication

Abstract

Cellular communication within a larger microenvironment is critical for a number of physiological processes. Within the bone marrow niche, direct cell communication between hematopoietic progenitor cells (HPCs) and osteoblasts provides essential cues for their proliferation and survival. While contact-dependent communication between HPCs and osteoblasts is known to be critical, the molecular pathways that govern this interaction are largely unclear. Moreover, the downstream events occurring at the HPC/osteoblast contact site remain uncharacterized, despite their major role in signaling and remodeling within the niche microenvironment. Using live cell imaging approaches, we found that intercellular transfer is a novel mode of cell communication within the bone marrow niche microenvironment. HPCs made prolonged contact with the osteoblast surface via a specialized membrane domain enriched in prominin 1, CD63 and rhodamine PE. At the contact site, portions of the HPC specialized domain containing these molecules were taken up by the osteoblast and internalized into long-lived, SARA-positive, signaling endosomes. This resulted in the downregulation of Smad signaling by the osteoblasts and a subsequent increase in the production of stromal-derived factor-1 (SDF-1), a chemokine responsible for HPC homing to bone marrow. These findings identify a novel mechanism involving intercellular transfer to signaling endosomes for targeted regulation of signaling and remodeling events within the osteoblastic niche microenvironment.