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The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation
Brenden W. Smith1, Sarah S. Rozelle, Amy Leung, Jessalyn Ubellacker, Ashley Parks, Shirley K. Nah, Deborah French, Paul Gadue, Stefano Monti, David H.K. Chui, Martin H. Steinberg, Andrew L. Frelinger, Alan D. Michelson6, Roger Theberge, Mark E. McComb, Catherine E. Costello, Darrell N. Kotton, Gustavo Mostoslavsky, David H. Sherr, and George J. Murphy,*
The evolutionarily conserved aryl hydrocarbon receptor (AhR) has been studied for its role in environmental chemical-induced toxicity. However, recent studies demonstrate that the AhR may regulate the hematopoietic and immune systems during development in a cell-specific manner. These results, together with the absence of an in vitro model system enabling production of large numbers of primary human hematopoietic progenitor cells (HPs) capable of differentiating into megakaryocyte- and erythroid-lineage cells, motivated us to determine if AhR modulation could facilitate both progenitor cell expansion and megakaryocyte and erythroid cell differentiation. Using a novel, iPSC-based, chemically-defined, serum and feeder cell-free culture system, we show that a functional AhR is expressed in HPs, and that remarkably, AhR activation in these HPs drives an unprecedented expansion of HPs, megakaryocyte- and erythroid-lineage cells. Further AhR modulation within rapidly expanding progenitor cell populations directs cell fate, with chronic AhR agonism permissive to erythroid differentiation and acute antagonism favoring megakaryocyte specification. These results highlight the development of a new, GMP-compliant platform for generating virtually unlimited numbers of human HPs with which to scrutinize red blood cell and platelet development, including the assessment of the role of this environmental chemical receptor in critical cell fate decisions during hematopoiesis.
