Blood Journal
Leading the way in experimental and clinical research in hematology

The aryl hydrocarbon receptor directs hematopoietic progenitor cell expansion and differentiation

  1. Brenden W. Smith1,
  2. Sarah S. Rozelle1,
  3. Amy Leung1,
  4. Jessalyn Ubellacker2,
  5. Ashley Parks2,
  6. Shirley K. Nah3,
  7. Deborah French4,
  8. Paul Gadue4,
  9. Stefano Monti5,
  10. David H.K. Chui1,
  11. Martin H. Steinberg1,
  12. Andrew L. Frelinger6,
  13. Alan D. Michelson6,
  14. Roger Theberge7,
  15. Mark E. McComb7,
  16. Catherine E. Costello7,
  17. Darrell N. Kotton3,
  18. Gustavo Mostoslavsky3,
  19. David H. Sherr2, and
  20. George J. Murphy1,*
  1. 1 Section of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA, United States;
  2. 2 Department of Environmental Health, Boston University School of Public Health, Boston, MA, United States;
  3. 3 Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, Boston, MA, United States;
  4. 4 Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, United States;
  5. 5 Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, United States;
  6. 6 Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;
  7. 7 Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA, United States
  1. * Corresponding author; email: gjmurphy{at}

Key points

  • A breakthrough involving the role of the aryl hydrocarbon receptor in the expansion and specification of hematopoietic progenitor cells.

  • This work sets a precedent for the utilization of an in vitro platform for the clinically relevant production of blood products.


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.

  • Submitted November 16, 2012.
  • Accepted May 6, 2013.