Both CD133(+) cells and monocytes provide significant improvement for hindlimb ischemia, although they do not transdifferentiate into endothelial cells.
To address a number of questions regarding the experimental use of bone marrow (BM) stem cells in hindlimb ischemia, including which is the best cell type (e.g., purified hematopoietic stem cell or monocytes), the best route of delivery [intramuscular (IM) or intravenous (IV)], and the mechanism of action (transdifferentiation or paracrine effects), we have compared the neovascularization capacities of CD133(+) stem cells and monocytes (CD11b(+)) from the BM of Tie2-GFP mice either via IV or IM in a murine severe hindlimb ischemia model. To test the effect of cytokine administration, an extra group received BM conditioned medium. Peripheral blood flow as well as capillary density and GPF-positivity detection in ischemic muscles was evaluated 7, 14, and 21 days postinjection. In addition, CD133(+) and CD11b(+) cells from transgenic animals were cultured in vitro with angiogenic media for 7, 14, and 21 days to assess GFP expression. In all four cell-treated groups, blood flow and capillary density significantly recovered compared with the mice that received no cells or conditioned medium. There were no differences with respect to cell types or administration routes, with the exception of a faster flow recovery in the CD133(+)-treated cell group. We did not find GFP(+) cells in the ischemic muscles and there was no GFP expression after in vitro proangiogenic culture. Our study shows that both purified CD133(+) stem cells and myeloid mononuclear cells, either IM or IV administered, have similar neoangiogenic ability. Nevertheless, transdifferentiation into endothelial cells is not the mechanism responsible for their beneficial effect.
Sanchez-Guijo
Fermin M
FM
Unidad de Terapia Celular, Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain. ferminsg@usal.es
Oterino
Enrique
E
Barbado
Maria-Victoria
MV
Carrancio
Soraya
S
Lopez-Holgado
Natalia
N
Muntion
Sandra
S
Hernandez-Campo
Pilar
P
Sanchez-Abarca
Luis-Ignacio
LI
Perez-Simon
Jose A
JA
San Miguel
Jesús F
JF
Briñon
Jesús G
JG
del Cañizo
Maria-Consuelo
MC
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000166:cytology / Q000502:physiology; D002196:Capillaries / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply* / Q000503:physiopathology; D007511:Ischemia / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology / Q000502:physiology / Q000637:transplantation*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D016896:Treatment Outcome
D000071916:AC133 Antigen; D015703:Antigens, CD; D015415:Biomarkers; D017077:Culture Media, Conditioned; D016207:Cytokines; D006023:Glycoproteins; D010455:Peptides; C000606024:Prom1 protein, mouse; D049452:Green Fluorescent Proteins