title: Engraftment defect of cytokine-cultured adult human mobilized CD34(+)  cells is related to reduced adhesion to bone marrow niche elements.
abstract: In vitro exposure of haematopoietic stem and progenitor cells (HSPC) to cytokines in expansion or gene therapy protocols reduces homing and engraftment in vivo. We have previously reported that this is related in part to altered tissue specificity of short-term homing, leading to loss of cells in non-haematopoietic tissues. Here we demonstrate that defective engraftment persists when cultured HSPC are transplanted by intrabone injection. Changes in engraftment function occur within 24 h of cytokine exposure, and are evident when engraftment is analysed solely in the injected bone. A novel ex vivo model of the bone marrow was developed, in which the attachment of infused HSPC in rodent long bones is reduced following culture with cytokines. Finally, cultured HSPC demonstrated reduced adhesion to N-cadherin, osteopontin and vascular cell-adhesion molecule-1, ligands present in bone marrow niches. These changes in adhesive function occur rapidly, and are not related to downregulation of the relevant receptors. Our findings suggest that cytokine exposure of adult human HSPC results in altered adhesion within bone marrow niches, further leading to reduced engraftment potential in vivo.
authors: Department of Haematology, Cancer Institute, University College of London, London, UK.
authors: Konstantina
authors: K
authors: Kallinikou
authors: Fernando
authors: F
authors: Anjos-Afonso
authors: Michael P
authors: MP
authors: Blundell
authors: Stuart J
authors: SJ
authors: Ings
authors: Michael J
authors: MJ
authors: Watts
authors: Adrian J
authors: AJ
authors: Thrasher
authors: David C
authors: DC
authors: Linch
authors: Dominique
authors: D
authors: Bonnet
authors: Kwee L
authors: KL
authors: Yong
mesh_terms: D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001853:Bone Marrow / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000637:transplantation; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D006085:Graft Survival / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D055153:Stem Cell Niche / Q000502:physiology*
chemical_list: D018952:Antigens, CD34; D003115:Colony-Stimulating Factors; D011994:Recombinant Proteins