Modulation of hematopoietic cell adhesion molecules by intraosseous injection: a strategy for enhanced homing and engraftment (2007)

A19 Traditional intravenous (IV) delivery of hematopoietic stem cell (HSC) results in only a small percentage of cells homing to bone marrow (BM). Direct delivery of BM cells has been applied via intracoronary injection in ischemic heart failure patients and intra-arterial injection in acute ischemic stroke patients, which besides suggesting BM’s trans-differentiation potential, also suggests the importance of the initial-encounter microenvironment. Clinical studies have shown that intraosseous (IO) injection of cord blood cells is associated with fast and complete hematologic recovery and almost absent acute graft versus host disease (GVHD). Unlike intracoronary and intra brain arterial injection, it is technically impossible to deliver HSC to all BM cavities. Underlying mechanisms of IO injection were being investigated in non-human primate model with donor BM cells labeled with PKH26. After IO injection, 13.12% donor cells were found within injection site BM, 5.75% were detected in non-injection side BM cavities, which was 2.71 fold higher that of IV recipients (2.12%, mean value of 6 separate experiments). IV injection results in 2.40 to 4.83 fold more donor cells trapped in organs like liver, spleen, heart, lung and kidney. Several cell adhesion molecules (CAM) that facilitate the penetration of cells through vascular walls were evaluated, like CD18, which mediates leukocyte rolling, adhesion on venules and leukocyte-endothelium interactions in microcirculation; and CD62L, which mediates the rolling of leukocytes on microvascular endothelium and transendothelial migration. Also evaluated was CD49d, which plays an important role to retain HSC within BM niches through the interaction between HSC and matrix components (Fibronectin). Expression of CD18 and CD62L within the injection BM was 82.12+ 5.55% and 7.97+ 5.79%, which was significantly lower than that in PB (96.70+ 3.35% and 36.47+ 7.94%). 53.69+ 14.28% donor cells expressed CD49d in injection-side BM, which was significantly higher than that in PB (18.40+ 6.73%). CAM expression profiles demonstrate that IO injection not only delivers HSC directly to BM, but also modulates, grooms and educates HSC to express CAM resulting in up-regulation of matrix maintaining factors and lower expression of rolling/ migration CAM. This results in better homing to other BM cavities even when the cells leak back into the blood stream, which helps explain higher donor cell percentage in non-injection side BM cavity and fewer cells found in peripheral organs in IO recipient. In non-human primate haploidentical HSCT with a modified reduced intensity conditioning regimen (Fludarabine, 30 mg/m2, day-5 to -3; cyclophosphamide, 50 mg/kg, day-5 to -2. Without total body irradiation), 3.30% donor cells were engrafted on day 15, which steadily increased to 19.06% on day 57 in IO recipient. This was in sharp contrast to the control IV recipients where no engraftment was detected up to day 180. Our results had demonstrated advantage of IO injection through environment modulation for BM cells, for CB cells that are not previously located in BM and have fewer BM homing factors expressed, the advantage may be even more prominent. CBT is a field whereby IO injection holds the most promise because of its fewer number of cells, lower BM homing potential and the relatively lower engraftment rate in adults.