Engraftment defect of cytokine-cultured adult human mobilized CD34+ cells is related to reduced adhesion to bone marrow niche elements

• Published in: British journal of haematology 2012-09, Vol.158 (6), p.778-787
• Main Authors: Kallinikou, Konstantina, Anjos-Afonso, Fernando, Blundell, Michael P., Ings, Stuart J., Watts, Michael J., Thrasher, Adrian J., Linch, David C., Bonnet, Dominique, Yong, Kwee L.
• Format: Article
• Language: English
• Subjects: adhesion; Adhesives; Adult; Animal models; Animals; Antigens, CD34 - analysis; Biological and medical sciences; Bone (long); Bone marrow; Bone Marrow - pathology; CD34 antigen; Cell Adhesion - physiology; Cell culture; Cell migration; Cells, Cultured - drug effects; Cells, Cultured - transplantation; Colony-Stimulating Factors - pharmacology; Cytokines; engraftment; G-CSF mobilized CD34+ cells; Gene therapy; Graft Survival - physiology; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - pathology; Humans; Male; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; N-Cadherin; Osteopontin; Rats; Rats, Sprague-Dawley; Receptor mechanisms; Recombinant Proteins - pharmacology; Specific Pathogen-Free Organisms; Stem Cell Niche - physiology; Stem cells; xenotransplantation model
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2012.09219.x

Summary 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.