Human marrow-isolated adult multilineage-inducible (MIAMI) cells protect against peripheral vascular ischemia in a mouse model.
OBJECTIVE
The treatment of peripheral vascular disease (PVD) with stem cells potentially offers a promising strategy. We tested marrow-isolated adult multilineage-inducible (MIAMI) cells to induce neovascularization in a mouse model of critical hindlimb ischemia (CLI).


METHODS
CLI was induced in the right hindlimb of Balb/C mice. One million MIAMI cells, normally grown at 3% O₂, were injected in the adductor muscle along the ischemic region. All animals (n = 11 per group) were immunosuppressed with cyclosporine daily for the entire period. Human foreskin fibroblast (HFF) cells and phosphate-buffered saline (PBS) were used as controls. Blood perfusion in the ischemic right and non-ischemic left hindlimbs was measured.


RESULTS
Compared with animals receiving HFF cells or PBS, MIAMI cells significantly improved blood perfusion, necrosis and inflammation in the ischemic limb. A fraction of injected MIAMI cells expressed CD31 and von Willebrand factor (vWF). MIAMI cells in vitro, under pro-angiogenic growth conditions, differentiated into endothelial-like cells and expressed endothelial markers such as CD31 and vWF, determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and CD31 and kinase insert domain receptor (KDR), determined by immunofluorescence. Moreover, MIAMI cells formed vascular endothelial-like tubules in the presence of matrigel. Bioplex immunoassay analysis showed increased secretion of angiogenic/anti-inflammatory factors by the MIAMI cells under 3% O₂ compared with 21% O₂, including monocyte chemoattractant protein-1 (MCP-1), fractalkine (Ftk), growth-related oncogene (GRO), vascular endothelial growth factor (VEGF), interleukin (IL)-6 and IL-8. Furthermore, transcripts for anti-inflammatory molecules stanniocalcin-1 (STC-1) and tumor necrosis factor-α-stimulated gene 6 (TSG-6) were up-regulated several fold.


CONCLUSIONS
MIAMI cells can be very useful for patients affected by CLI. MIAMI cells promote blood vessel formation and reduce inflammation and necrosis in ischemic tissue.
Rahnemai-Azar
Amirali
A
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
D'Ippolito
Gianluca
G
Gomez
Lourdes A
LA
Reiner
Teresita
T
Vazquez-Padron
Roberto I
RI
Perez-Stable
Carlos
C
Roos
Bernard A
BA
Pham
Si M
SM
Schiller
Paul C
PC
D053687:Adult Stem Cells / Q000502:physiology* / Q000637:transplantation*; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006614:Hindlimb / Q000098:blood supply* / Q000293:injuries; D006801:Humans; D007249:Inflammation / Q000628:therapy; D007511:Ischemia / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D018919:Neovascularization, Physiologic; D016491:Peripheral Vascular Diseases / Q000628:therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
D042501:Angiogenic Proteins; D016207:Cytokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014841:von Willebrand Factor; D040301:Vascular Endothelial Growth Factor Receptor-2