title: 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.
authors.affiliation: Department of Neurology, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Moniche
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Jose-Ramon
authors.initials: JR
authors.lastname: Gonzalez-Marcos
authors.forename: Magdalena
authors.initials: M
authors.lastname: Carmona
authors.forename: Pilar
authors.initials: P
authors.lastname: Piñero
authors.forename: Ildefonso
authors.initials: I
authors.lastname: Espigado
authors.forename: Aurelio
authors.initials: A
authors.lastname: Cayuela
authors.forename: Irene
authors.initials: I
authors.lastname: Escudero
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: de la Torre-Laviana
authors.forename: Cristina
authors.initials: C
authors.lastname: Boada
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
authors.forename: Antonio
authors.initials: A
authors.lastname: Mayol
authors.forename: Maria-Dolores
authors.initials: MD
authors.lastname: Jimenez
authors.forename: Alberto
authors.initials: A
authors.lastname: Gil-Peralta
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gonzalez
mesh_terms: D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D000077214:Becaplermin; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation; D002452:Cell Count; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood*; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D020574:Proto-Oncogene Proteins c-sis / Q000097:blood*; D020521:Stroke / Q000097:blood* / Q000201:enzymology / Q000628:therapy*
chemical_list: D018952:Antigens, CD34; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9