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Blood, 15 March 2008, Vol. 111, No. 6, pp. 2953-2961.
Prepublished online as a Blood First Edition Paper on December 4, 2007; DOI 10.1182/blood-2007-10-117366.
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Submitted October 9, 2007
Accepted November 28, 2007
Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell-derived hematopoietic progenitor cells
Kun-Ming Chan, Sabrina Bonde, Hannes Klump, and Nicholas Zavazava*
Department of Internal Medicine, University of Iowa and Veteran Affairs Medical Center, Iowa City, Iowa, United States
Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
Department of Experimental Hematology, Hannover Medical School, Hannover, Germany
Immunology Graduate Program, University of Iowa, Iowa City, Iowa, United States
* Corresponding author; email: nicholas-zavazava{at}uiowa.edu.
The ability of embryonic stem (ES) cells to form cells and tissues from all three germ layers can be exploited to generate cells that can be used to treat diseases. In particular, successful generation of hematopoietic cells from ES cells could provide safer and less immunogenic cells than bone marrow cells, which require severe host preconditioning when transplanted across MHC barriers. Here, we exploited the self-renewal properties of ectopically expressed HOXB4, a homeobox transcription factor, to generate hematopoietic progenitor cells (HPCs) that successfully induce high level mixed chimerism and long-term engraftment in recipient mice. The HPCs partially restored splenic architecture in Rag2-/- c-/- immunodeficient mice. Additionally, HPC-derived newly generated T cells were able to mount a peptide-specific response to lymphocytic choriomeningitis virus (LCMV) and specifically secreted IL-2 and IFN- upon CD3 stimulation. In addition, HPC-derived antigen presenting cells (APCs) in chimeric mice efficiently presented viral antigen to wild type (WT) T cells. These results demonstrate for the first time that leukocytes derived from ES cells ectopically expressing HOXB4 are immunologically functional opening up new opportunities for the use of ES cell-derived HPCs in the treatment of hematological and immunological diseases.
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