Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell-derived hematopoietic progenitor cells.
The ability of embryonic stem (ES) cells to form cells and tissues from all 3 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 major histocompatibility complex 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(-/-)gamma(c)(-/-)-immunodeficient mice. In addition, HPC-derived newly generated T cells were able to mount a peptide-specific response to lymphocytic choriomeningitis virus and specifically secreted interleukin-2 and interferon-gamma upon CD3 stimulation. In addition, HPC-derived antigen presenting cells in chimeric mice efficiently presented viral antigen to wild-type 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 hematologic and immunologic diseases.
Department of Internal Medicine, University of Iowa and Veteran Affairs Medical Center, Iowa City, Iowa 52242, USA.
Kun-Ming
KM
Chan
Sabrina
S
Bonde
Hannes
H
Klump
Nicholas
N
Zavazava
D000818:Animals; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D046528:Chimerism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006410:Hematopoiesis / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D017252:CD3 Complex; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; D014157:Transcription Factors