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SummaryMesenchymal stem cells (MSC) are being used increasingly in clinical trials for a range of regenerative and inflammatory diseases. Bone marrow is the traditional source but is relatively inaccessible in large volume. MSC have now been derived from tissues other than bone marrow including placenta and adipose tissue. We have used placenta obtained after delivery as a source of MSC and have been unable to detect any marked differences from marrow-derived MSC in terms of cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability. This report described our manufacturing process for isolating and expanding placenta-derived human MSC and their safe infusion into the first patient in a clinical trial program of human placenta-derived MSC.

SDF-1 and CXCR4 are an important chemokine ligand/receptor pair, which play a crucial role in numerous biological processes including hematopoiesis, cardiogenesis, vasculogenesis, neuronal development and immune cell trafficking. They have also been implicated in various pathological conditions such as cancer, infection with the human immunodeficiency virus (HIV) and various inflammatory conditions. Numerous pharmacological agents exist that can modulate SDF-1/CXCR4-induced responses both in vitro and in vivo. The usefulness of these agents in affecting the outcome of pathological conditions influenced by the SDF-1/CXCR4 axis is currently being investigated. Whilst some of these compounds have been shown to be safe and well tolerated in phase 1 clinical trials, the full repercussions of SDF-1/CXCR4 inhibition or stimulation on normal physiological functions are yet to be appreciated. Inhibition of the SDF-1/CXCR4 axis may have positive effects in regulating tumour metastasis and growth, however, this may also negate immunological responses through dysregulated lymphocyte trafficking and contribute to disruption of hematopoiesis. As with any therapy, the usefulness of this type of intervention will require a balance between its positive effect on the disease outcome and deleterious effects on normal physiological functions. A greater understanding of the role of SDF-1 and CXCR4 in the body will allow greater manipulation of this important biological axis to affect disease outcome. Greater knowledge of the SDF-1 interaction with its receptor and the structural elements within CXCR4 mediating the different signalling events, resulting in SDF-1-induced responses, will also enhance future drug design.

Mobilization of stem cells with pegylated granulocyte colony-stimulating factor (peg-G-CSF) modulates donor T- and natural killer T-cell (NKT-cell) functions, thus separating graft-versus-host from graft-versus-leukemia disease in animal models. We report a phase I/II study that analyzed the feasibility of mobilizing stem cells from normal donors with peg-G-CSF and the ability of these cells to restore hematopoiesis in allogeneic transplant recipients after myeloablative conditioning. Administration of 6 mg of peg-G-CSF resulted in suboptimal stem cell mobilization, with a peak peripheral blood CD34+ count of 29+/-5/microL. Apheresis 4 days after peg-G-CSF yielded 2.7+/-.4x10(6) CD34+ cells/kg recipient weight, and all donors required a second collection on day 5 to yield a total of 4.2+/-.5x10(6) CD34+ cells/kg recipient weight. After escalation of the dose to 12 mg, the peak CD34+ count was 99+/-11/microL and 12 of 13 donors collected sufficient stem cells for transplantation in a single apheresis (8.9+/-1.4x10(6) CD34+ cells/kg recipient weight). Late transient increases in serum hepatic transaminases were noted, but other side effects (predominantly bone pain) were otherwise similar to those seen in donors mobilized with standard G-CSF. Median neutrophil and platelet engraftments occurred on days 18 and 14, respectively, after transplantation and were identical to those seen with in recipients of grafts mobilized with standard G-CSF. With a median follow-up of 357 days, the incidence of grade II-IV acute graft-versus-host disease was 50% and there have been no relapses to date. Mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12 mg results in mobilization characteristics similar to those of standard G-CSF.