ShRNA-mediated decreases in c-met levels affect the differentiation potential of human mesenchymal stem cells and reduce their capacity for tissue repair

Ivana Rosová, Daniel Link, Jan Nolta

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Mesenchymal stem cells/marrow stromal cells (MSC) are adult multipotent cells that can augment tissue repair. We previously demonstrated that culturing MSC in hypoxic conditions causes upregulation of the hepatocyte growth factor (HGF) receptor c-Met, allowing them to respond more robustly to HGF. MSC preconditioned in hypoxic environments contributed to restoration of blood flow after an ischemic injury more rapidly than MSC cultured in normoxic conditions. We now investigated the specific role of HGF/c-Met signaling in MSC function. An shRNA-mediated knockdown (KD) of c-Met in MSC did not alter their phenotypic profile, proliferation, or viability in vitro. However, we determined that while HGF/c-Met signaling does not play a role in the adipogenic differentiation of the cells, the disruption of this signaling pathway inhibited the ability of MSC to differentiate into the osteogenic and chondrogenic lineages. We next assessed the impact of c-Met KD on human MSC function in a xenogeneic hindlimb ischemia injury model. A 70% KD of c-Met in MSC resulted in a significant decrease in their capacity to regenerate blood flow to the ischemic limb, as compared to the MSC transduced with control shRNA. MSC with only a 60% KD of c-Met exhibited an intermediate capacity to restore blood flow, suggesting that MSC function is sensitive to the dosage of c-Met signaling. The current study highlights the significance of HGF/c-Met signaling in the capacity of MSC to restore blood flow after an ischemic injury and in their ability to differentiate into the osteogenic and chondrogenic lineages.

Original languageEnglish (US)
Pages (from-to)2627-2639
Number of pages13
JournalTissue Engineering - Part A
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2010

Fingerprint

Stromal Cells
Stem cells
Mesenchymal Stromal Cells
Hepatocyte Growth Factor
Repair
Bone Marrow
Tissue
Blood
Small Interfering RNA
Proto-Oncogene Proteins c-met
Restoration
Cells
Intercellular Signaling Peptides and Proteins
Hepatocytes
Wounds and Injuries
Hindlimb
Cell Differentiation
Up-Regulation
Ischemia
Extremities

ASJC Scopus subject areas

  • Bioengineering
  • Biochemistry
  • Biomedical Engineering
  • Biomaterials
  • Medicine(all)

Cite this

ShRNA-mediated decreases in c-met levels affect the differentiation potential of human mesenchymal stem cells and reduce their capacity for tissue repair. / Rosová, Ivana; Link, Daniel; Nolta, Jan.

In: Tissue Engineering - Part A, Vol. 16, No. 8, 01.08.2010, p. 2627-2639.

Research output: Contribution to journalArticle

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