PMID- 20367286
OWN - NLM
STAT- MEDLINE
DCOM- 20110125
LR  - 20211020
IS  - 1937-335X (Electronic)
IS  - 1937-3341 (Print)
IS  - 1937-3341 (Linking)
VI  - 16
IP  - 8
DP  - 2010 Aug
TI  - shRNA-mediated decreases in c-Met levels affect the differentiation potential of 
      human mesenchymal stem cells and reduce their capacity for tissue repair.
PG  - 2627-39
LID - 10.1089/ten.TEA.2009.0363 [doi]
AB  - 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.
FAU - Rosova, Ivana
AU  - Rosova I
AD  - Division of Oncology, Stem Cell Biology Program, Washington University School of 
      Medicine, St. Louis, Missouri, USA.
FAU - Link, Daniel
AU  - Link D
FAU - Nolta, Jan A
AU  - Nolta JA
LA  - eng
GR  - R01HL073256/HL/NHLBI NIH HHS/United States
GR  - R01 DK061848-09/DK/NIDDK NIH HHS/United States
GR  - R01 DK061848/DK/NIDDK NIH HHS/United States
GR  - S10 RR026825-01/RR/NCRR NIH HHS/United States
GR  - 2R01DK53041/DK/NIDDK NIH HHS/United States
GR  - R01 HL073256/HL/NHLBI NIH HHS/United States
GR  - 2R01DK61848/DK/NIDDK NIH HHS/United States
GR  - S10 RR026825/RR/NCRR NIH HHS/United States
GR  - R01 HL073256-06/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Tissue Eng Part A
JT  - Tissue engineering. Part A
JID - 101466659
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Cell Culture Techniques/methods
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Feasibility Studies
MH  - Genetic Enhancement/methods
MH  - Hindlimb/*blood supply/surgery
MH  - Humans
MH  - Ischemia/metabolism/*surgery
MH  - Mesenchymal Stem Cell Transplantation/*methods
MH  - Mesenchymal Stem Cells/*cytology/*metabolism
MH  - Mice
MH  - Mice, SCID
MH  - Proto-Oncogene Proteins c-met/genetics/*metabolism
MH  - RNA, Small Interfering/*genetics
MH  - Regeneration/physiology
MH  - Treatment Outcome
MH  - Up-Regulation/physiology
PMC - PMC2947453
EDAT- 2010/04/07 06:00
MHDA- 2011/01/28 06:00
PMCR- 2011/08/01
CRDT- 2010/04/07 06:00
PHST- 2010/04/07 06:00 [entrez]
PHST- 2010/04/07 06:00 [pubmed]
PHST- 2011/01/28 06:00 [medline]
PHST- 2011/08/01 00:00 [pmc-release]
AID - 10.1089/ten.tea.2009.0363 [pii]
AID - 10.1089/ten.TEA.2009.0363 [doi]
PST - ppublish
SO  - Tissue Eng Part A. 2010 Aug;16(8):2627-39. doi: 10.1089/ten.TEA.2009.0363.