Impaired bone marrow homing of cytokine-activated CD34+ cells in the NOD/SCID model.
The reduced engraftment potential of hematopoietic stem/progenitor cells (HSPCs) after exposure to cytokines may be related to the impaired homing ability of actively cycling cells. We tested this hypothesis by quantifying the short-term homing of human adult CD34+ cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) animals. We show that the loss of engraftment ability of cytokine-activated CD34+ cells is associated with a reduction in homing of colony-forming cells (CFCs) to bone marrow (BM) at 24 hours after transplantation (from median 2.8% [range, 1.9%-6.1%] to 0.3% [0.0%-0.7%]; n = 3; P < .01), coincident with an increase in CFC accumulation in the lungs (P < .01). Impaired BM homing of cytokine-activated cells was not restored by using sorted cells in G0G1 or by inducing cell cycle arrest at the G1/S border. Blocking Fas ligation in vivo did not increase the BM homing of cultured cells. Finally, we tested cytokine combinations or culture conditions previously reported to restore the engraftment of cultured cells but did not find that any of these was able to reverse the changes in homing behavior of cytokine-exposed cells. We suggest that these changes in homing and, as a consequence, engraftment result from the increased migratory capacity of infused activated cells, leading to the loss of selectivity of the homing process.
Ahmed
Forhad
F
Department of Haematology, Royal Free and University College Medical School, London, WC1E 6HX, United Kingdom.
Ings
Stuart J
SJ
Pizzey
Arnold R
AR
Blundell
Michael P
MP
Thrasher
Adrian J
AJ
Ye
Hong T
HT
Fahey
Anne
A
Linch
David C
DC
Yong
Kwee L
KL
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000737:chemistry / Q000166:cytology*; D002453:Cell Cycle / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D003470:Culture Media / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016511:Severe Combined Immunodeficiency / Q000473:pathology*
D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D003470:Culture Media; C515256:Cxcl12 protein, mouse; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins