Expansion of haematopoietic stem cells from normal donors and bone marrow failure patients by recombinant hoxb4.
In this study six versions of recombinant human hoxb4 proteins were produced and their effectiveness evaluated in expanding human haematopoietic stem and progenitor cells in vitro and in vivo. An N-terminal-tat and C-terminal histidine-tagged version of hoxb4 (T-hoxb4-H) showed the highest activity in expanding colony forming cells (CFCs) and long-term culture-initiating cells (LTC-ICs) when used at 50 nmol/l concentration in cell culture. Human cord blood CD34(+) cells cultured with 50 nmol/l T-hoxb4-H showed a significant increase in severe-combined immunodeficient mouse-repopulating cells (SRCs). In a mouse model of immune-mediated bone marrow (BM) failure, T-hoxb4-H showed an additive effect with cyclosporine in alleviating pancytopenia. In addition, T-hoxb4-H expanded CFC and LTC-IC on BM samples from patients with refractory severe aplastic anaemia and myelodysplastic syndromes: after culturing with 50 nmol/l T-hoxb4-H for 4 d, BM cells from 10 of the 11 patients showed increases in CFC and LTC-IC, and the increase in LTC-IC was statistically significant in samples from four patients. Recombinant human hoxb4 could be a promising therapeutic agent for BM failure.
Tang
Yong
Y
Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-1202, USA.
Chen
Jichun
J
Young
Neal S
NS
D000741:Anemia, Aplastic / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D018398:Homeodomain Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009190:Myelodysplastic Syndromes / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000494:pharmacology* / Q000627:therapeutic use
D018952:Antigens, CD34; C090460:HOXB4 protein, human; D018398:Homeodomain Proteins; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D014157:Transcription Factors; D016572:Cyclosporine