Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization

Liying Cai, Brian H. Johnstone, Todd G. Cook, Zhong Liang, Dmitry Traktuev, Kenneth Cornetta, David Ingram, Elliot Rosen, Keith L. March

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

The use of adipose-derived stem/stromal cells (ASCs) for promoting repair of tissues is a promising potential therapy, but the mechanisms of their action are not fully understood. We and others previously demonstrated accelerated reperfusion and tissue salvage by ASCs in peripheral ischemia models and have shown that ASCs secrete physiologically relevant levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor. The specific contribution of HGF to ASC potency was determined by silencing HGF expression. RNA interference was used to downregulate HGF expression. A dual-cassette lentiviral construct expressing green fluorescent protein (GFP) and either a small hairpin RNA specifically targeted to HGF mRNA (shHGF) or an inactive control sequence (shCtrl) were used to stably transduce ASCs (ASC-shHGF and ASCshCtrl, respectively). Transduced ASC-shHGF secreted >80% less HGF, which led to a reduced ability to promote survival, proliferation, and migration of mature and progenitor endothelial cells in vitro. ASC-shHGF were also significantly impaired, compared with ASC-shCtrl, in their ability to promote reperfusion in a mouse hindlimb ischemia model. The diminished ability of ASCs with silenced HGF to promote reperfusion of ischemic tissues was reflected by reduced densities of capillaries in reperfused tissues. In addition, fewer GFP+ cells were detected at 3 weeks in ischemic limbs of mice treated with ASC-shHGF compared with those treated with ASC-shCtrl. These results indicate that production of HGF is important for the potency of ASCs. This finding directly supports the emerging concept that local factor secretion by donor cells is a key element of cell-based therapies.

Original languageEnglish
Pages (from-to)3234-3243
Number of pages10
JournalStem Cells
Volume25
Issue number12
DOIs
StatePublished - Dec 2007

Fingerprint

Hepatocyte Growth Factor
Stromal Cells
Stem Cells
Reperfusion
Green Fluorescent Proteins
Ischemia
Hindlimb
Cell- and Tissue-Based Therapy
RNA Interference
Vascular Endothelial Growth Factor A
Small Interfering RNA
Adipose Tissue
Down-Regulation
Extremities

Keywords

  • Adipose-derived stem cells
  • Hepatocyte growth factor
  • Paracrine
  • RNA interference

ASJC Scopus subject areas

  • Cell Biology

Cite this

Suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. / Cai, Liying; Johnstone, Brian H.; Cook, Todd G.; Liang, Zhong; Traktuev, Dmitry; Cornetta, Kenneth; Ingram, David; Rosen, Elliot; March, Keith L.

In: Stem Cells, Vol. 25, No. 12, 12.2007, p. 3234-3243.

Research output: Contribution to journalArticle

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