Intra-Arterial Bone Marrow Mononuclear Cell Transplantation Correlates with GM-CSF, PDGF-BB, and MMP-2 Serum Levels in Stroke Patients: Results from a Clinical Trial

Abstract

Bone marrow mononuclear cell (BM-MNC) intra-arterial transplantation improves recovery in experimental models of ischemic stroke through secretion of cytokines and growth factors (GFs), enhancing neoangiogenesis, and enhancing neuroplasticity. In this study, we tested whether BM-MNC transplantation in stroke patients induces changes in serum levels of cytokines and GFs. A phase I/II trial was conducted in middle cerebral artery (MCA) stroke patients with autologous intra-arterial BM-MNC transplantation between 5 and 9 days after stroke. Follow-up was done for up to 6 months. Eight cases and nine controls were included, and the serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), β nerve growth factor (β-NGF), and matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) were measured before and 4, 8, and 90 days after transplantation. The correlation of these serum levels with dose of cells and clinical outcomes was studied. A total of 1.59 × 10(8) (±1.21 × 10(8)) BM-MNCs were injected in cases; of them 3.38 × 10(6) (±2.33 × 10(6)) were CD34(+) cells. There was a positive correlation between total BM-MNCs injected and levels of GM-CSF and PDGF-BB at 90 days after transplantation (r = 0.929, p = 0.001 and r = 0.714, p = 0.047, respectively), and a negative correlation between total CD34(+) cells injected and MMP-2 levels at 4 days after transplantation (r = -0.786, p = 0.036). Lower plasma levels of MMP-2 at 4 days and higher levels of PDGF-BB at 90 days were associated with better functional outcomes during follow-up (p = 0.019 and p = 0.037, respectively). When administered intra-arterially in subacute MCA stroke patients, BM-MNCs seem to induce changes in serum levels of GM-CSF, PDGF-BB, and MMP-2, even 3 months after transplantation, which could be associated with better functional outcomes. This manuscript is published as part of the International Association of Neurorestoratology (IANR) special issue of Cell Transplantation.

Stem Cell‐Based Therapies for Ischemic Stroke: Preclinical Results and the Potential of Imaging‐Assisted Evaluation of Donor Cell Fate and Mechanisms of Brain Regeneration

“…Subsequently, these cells have been used in several clinical trials. IA administration of these cells was safe and showed an improved clinical outcome . IV delivery of these cells also appeared safe, although no clinical improvement was observed in the study by Prasad et al., whereas Savitz et al.…”

“…IA administration of these cells was safe and showed an improved clinical outcome. 280,281 IV delivery of these cells also appeared safe, 282 although no clinical improvement was observed in the study by Prasad et al, 283 whereas Savitz et al were able to show an improved functional outcome. 282 Despite these encouraging results, in depth in vitro evidence on the underlying mechanisms of action is largely unknown.…”

Vascular precursor cells in tissue injury repair

“…In patients with stroke, treatment with G-CSF has been shown to substantially increase CD34 + cells in the circulation 315,316 , which is associated with a tendency toward reduction in ischemic lesion in the brain 316 . Several phase I clinical trials have been completed involving intra-arterial or intravenous transplantation of autologous marrow mononuclear cells, including CD34 + precursor cells, in patients with stroke 317,318 . The results suggest that this therapy is feasible and seems to be safe.…”

Current Stage and Future Perspective of Stem Cell Therapy in Ischemic Stroke

“…However, other clinical trials that search for safety and afficacy of different stem cells are ongoing now [41,47]. Other clinical trials that were completed until now did not report tumor formation in humans after stem cell delivery [40].…”

“…Other clinical trials using bone marrow derived stem cell (BMSC) in stroke have shown the feasibility and safety of the approach [36][37][38][39]. Moniche et al showed that the BMSC in subacute Middle Cerebral Artery (MCA) stroke patients could induce changes in serum levels of GranulocyteMacrophage Colony-Stimulating Factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), and matrix metalloproteinases 2 (MMP-2), which could induce an improved functional outcomes [40].…”