Collaborative Research NSF-ANR: Mechanisms of Terminal Erythroid Enucleation

University Of Illinois At Chicago, Chicago IL

Investigators

Abstract

This award aims to describe the physical mechanisms at play in enucleation during mammalian erythropoiesis, which is the process of generation of red blood cells (RBCs). The objective is to elucidate the role of the mechanical constraints in the bone marrow on the extrusion and detachment of the nucleus of the erythroid precursor. This role is currently poorly understood, which holds back progress in fundamental studies of erythropoiesis. This project will not only advance our fundamental understanding of erythroid enucleation but provide new knowledge for improving in vitro red blood cell production by engineering mechanical environments to overcome ineffective enucleation. This project will be the first to connect the internal and external forces that drive erythroid enucleation, and to incorporate mechanosensing of the cell. There are several barriers to reveal the mechanisms of intrinsic and extrinsic enucleation cues. First, it is difficult to fabricate an in vitro device that mimics the crowded environment of the bone marrow with extremely small inter-endothelial gaps that allows live imaging of enucleation. Second, the computational modeling for quantifying forces is challenging due to the strong interactions in small gaps and the prediction of forces across molecular to cellular scales. The interdisciplinary team of scientists in this project (consisting of three leading groups: a biologist in erythropoiesis at Northwestern University, a physicist in microfluidics in CNRS Marseille, France, and an engineer in multiscale modeling at the University of Illinois at Chicago) is uniquely positioned to overcome such barriers and elucidate the mechanisms of intrinsic and extrinsic enucleation cues. This project will have practical impact in the biomedical field, such as transfusion medicine in which rare blood types often have limited supplies. The bottleneck of in vivo RBC production is the ineffective enucleation, and the knowledge obtained from this study will help overcome this bottleneck and could potentially revolutionize the industry of blood supply. The project will also have educational and training outcomes, as results and techniques obtained from this project will be incorporated into courses the Principal Investigators teach. One PhD student and two postdoctoral fellows will be trained through the support of this project. This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigators and ANR funds the partner in France. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.