Human marrow-isolated adult multilineage-inducible (MIAMI) cells protect against peripheral vascular ischemia in a mouse model

Cytotherapy. 2011 Feb;13(2):179-92. doi: 10.3109/14653249.2010.515579. Epub 2010 Sep 15.

Abstract

Background aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult Stem Cells / physiology*
  • Adult Stem Cells / transplantation*
  • Angiogenic Proteins / metabolism
  • Animals
  • Bone Marrow Cells
  • Cell Differentiation
  • Cytokines / metabolism
  • Fluorescent Antibody Technique
  • Hindlimb / blood supply*
  • Hindlimb / injuries
  • Humans
  • Inflammation / therapy
  • Ischemia / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Necrosis
  • Neovascularization, Physiologic*
  • Peripheral Vascular Diseases / therapy*
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Regional Blood Flow
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cell Transplantation
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • von Willebrand Factor / genetics
  • von Willebrand Factor / metabolism

Substances

  • Angiogenic Proteins
  • Cytokines
  • Platelet Endothelial Cell Adhesion Molecule-1
  • von Willebrand Factor
  • Vascular Endothelial Growth Factor Receptor-2