Ex vivo treatment of proliferating human cord blood stem cells with stroma-derived factor-1 enhances their ability to engraft NOD/SCID mice.
Ex vivo proliferation of hematopoietic stem cells (HSCs) is important for cellular and gene therapy but is limited by the observation that HSCs do not engraft as they transit S/G(2)/M. Recently identified candidate inhibitors of human HSC cycling are transforming growth factor-beta(1) (TGF-beta(1)) and stroma-derived factor-1 (SDF-1). To determine the ability of these factors to alter the transplantability of human HSCs proliferating in vitro, lin(-) cord blood cells were first cultured for 96 hours in serum-free medium containing Flt3 ligand, Steel factor, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor. These cells were then transferred to medium containing Steel factor and thrombopoietin with or without SDF-1 and/or TGF-beta(1) for 48 hours. Exposure to SDF-1 but not TGF-beta(1) significantly increased (> 2-fold) the recovery of HSCs able to repopulate nonobese diabetic/severe combined immunodeficiency mice. These results suggest new strategies for improving the engraftment activity of HSCs stimulated to proliferate ex vivo.
Glimm
Hanno
H
Terry Fox Laboratory, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada.
Tang
Patrick
P
Clark-Lewis
Ian
I
von Kalle
Christof
C
Eaves
Connie
C
D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology; D006085:Graft Survival / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD / Q000502:physiology*; D016513:Mice, SCID / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003470:Culture Media; C515256:Cxcl12 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1