Collaborative Research NSF-ANR: Mechanisms of terminal erythroid enucleation – RedEnuc

The process of red blood cell (RBC) production is named erythropoiesis. Erythroblasts are precursor cells of RBCs. In mammals, during their maturation process towards RBCs, erythroblasts lose their nuclei (enucleation). While studies identified regulators of the three stages of enucleation (nuclear polarization, extrusion, and detachment from the nascent reticulocyte), its detailed mechanisms are still unknown, especially in the final stage associated with reticulocytes passing through the narrow bone marrow and splenic inter-endothelial slits to reach the bloodstream.
It is nowadays known that mechanical forces act in the enucleation process, but their role in not understood yet, essentially because we lack experimental approaches allowing to replicate in vitro the environmental conditions of the reticulocyte in the bone marrow (or spleen). We propose two hypotheses on these mechanical forces:
1) The bone marrow is a highly crowded environment in which erythroblasts collide with –and are squeezed by– their numerous neighbors, this external stress induces a mechano-sensitive response of the erythroblasts which in turn generate internal forces that drive nucleus expulsion;
2) When nascent reticulocytes pass through the inter-endothelial slits, they are subjected to other mechanical forces, generated both by the extreme confinement in the narrow slits and by the blood flow on the other side of the slits.
To quantitatively elucidate the physical mechanisms at play in enucleation, our consortium proposes an interdisciplinary approach combining a physics component based on unique microfluidic device mimicking the bone marrow inter-endothelial slits, a cell biology component by comparing normal erythroblasts and erythroblasts deficient in mechanosensitivity actors, and a computational component to simulate the internal/external forces applied on the cell and its nucleus.