Sj Ings

Cord blood progenitor cells have greater transendothelial migratory activity and increased responses to SDF‐1 and MIP‐3β compared with mobilized adult progenitor cells

When cord blood is used as a source of haemopoietic stem cells for transplantation, fewer cells are required per kg of recipient. This greater engraftment efficiency of cord blood cells may relate to an increased ability to traverse sinusoidal endothelium, a crucial step in the homing of stem cells. We report that freshly isolated cord blood progenitors migrated more efficiently than mobilized adult cells. Cord blood progenitors responded rapidly to growth factor stimulation with an increase in migratory ability within 24 h whereas mobilized adult cells responded only after 72 h (P < 0.01). Cord blood cells also exited G0/G1 rapidly; after 24 h of growth factor exposure, 20.2 ± 1.2% of cord blood CD34+ cells were in S + G2/M compared to 6.9 ± 1.2% of adult CD34+ cells (P < 0.01). Proliferating CFC migrated more efficiently (13.3 ± 3.4% for GM‐CFC) than non‐proliferating CFC (1.4 ± 0.5%, P < 0.01) as determined using a 3H‐thymidine suicide assay. Cord blood progenitor cells also demonstrated a greater transmigratory response to chemokine stimulation compared with adult cells; this was manifested as a differential response of freshly isolated cells to SDF‐1, and of growth factor activated cells to MIP‐3β. Finally, cord blood CD34+ cells express higher levels of the chemokine receptor for SDF‐1, CXCR4, when compared with mobilized adult CD34+ cells (P < 0.05).

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

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.