Background and Purpose-Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke. We aimed to assess the safety, feasibility, and biological effects of autologous BM-MNC transplantation in patients with stroke. Methods-A single-blind (outcomes assessor) controlled Phase I/II trial was conducted in patients with middle cerebral artery stroke. Autologous BM-MNCs were injected intra-arterially between 5 and 9 days after stroke. Follow-up was done for up to 6 months and blood samples were collected for biological markers. The primary outcome was safety and feasibility of the procedure. The secondary outcome was improvement in neurological function. Results-Ten cases (BM-MNC-treated) and 10 control subjects (BM-MNC-nontreated) were consecutively included.Mean National Institutes of Health Stroke Scale before the procedure was 15.6. Mean BM-MNCs injected were 1.59ϫ10 8 . There was no death, stroke recurrence, or tumor formation during follow-up, although 2 cases had an isolate partial seizure at 3 months. After transplantation, higher plasma levels of beta nerve growth factor (␤-nerve growth factor) were found compared with control subjects (Pϭ0.02). There were no significant differences in neurological function at 180 days. A trend to positive correlation between number of CD34ϩ cells injected and Barthel Index was found (rϭ0.56, Pϭ0.09). Conclusions-Intra-arterial BM-MNC transplantation in subacute ischemic stroke is feasible and seems to be safe. Larger randomized trials are needed to confirm the safety and elucidate the efficacy of BM-MNC transplantation. Clinical Trial Registration-URL-www.clinicaltrials.gov. Unique identifier: NCT00761982.

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The online version of this article has a Supplementary Appendix. BackgroundThe number of CD34 + cells mobilized from bone marrow to peripheral blood after administration of granulocyte colony-stimulating factor varies greatly among healthy donors. This fact might be explained, at least in part, by constitutional differences in genes involved in the interactions tethering CD34 + cells to the bone marrow. Design and MethodsWe analyzed genetic characteristics associated with CD34 + cell mobilization in 112 healthy individuals receiving granulocyte colony-stimulating factor (filgrastim; 10 μg/kg; 5 days). ResultsGenetic variants in VCAM1 and in CD44 were associated with the number of CD34 + cells in peripheral blood after granulocyte colony-stimulating factor administration (P=0.02 and P=0.04, respectively), with the quantity of CD34 + cells ¥10 6 /kg of donor (4.6 versus 6.3; P<0.001 and 7 versus 5.6; P=0.025, respectively), and with total CD34 + cells ¥10 6 (355 versus 495; P=0.002 and 522 versus 422; P=0.012, respectively) in the first apheresis. Of note, granulocyte colonystimulating factor administration was associated with complete disappearance of VCAM1 mRNA expression in peripheral blood. Moreover, genetic variants in granulocyte colony-stimulating factor receptor (CSF3R) and in CXCL12 were associated with a lower and higher number of granulocyte colony-stimulating factor-mobilized CD34 + cells/μL in peripheral blood (81 versus 106; P=0.002 and 165 versus 98; P=0.02, respectively) and a genetic variant in CXCR4 was associated with a lower quantity of CD34 + cells ¥10 6 /kg of donor and total CD34 + cells ¥10 6 (5.3 versus 6.7; P=0.02 and 399 versus 533; P=0.01, respectively). ConclusionsIn conclusion, genetic variability in molecules involved in migration and homing of CD34 + cells influences the degree of mobilization of these cells.

Infusion of previously frozen stem cells may achieve similar overall outcomes compared to fresh infusion, allowing to program donor apheresis and transplantation. However, cryopreservation might influence on the different pattern of aGVHD, issue that deserves further studies.