PMID- 18687993
OWN - NLM
STAT- MEDLINE
DCOM- 20081128
LR  - 20181201
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Linking)
VI  - 26
IP  - 10
DP  - 2008 Oct
TI  - Constitutive expression of HIF-1alpha and HIF-2alpha in bone marrow stromal cells 
      differentially promotes their proangiogenic properties.
PG  - 2634-43
LID - 10.1634/stemcells.2008-0369 [doi]
AB  - Bone marrow stromal cells (BMSCs) contain progenitors capable of participating in 
      postnatal angiogenesis. Hypoxia-inducible factors (HIFs) mediate endothelial 
      activation by driving the expression of multiple angiogenic factors. We explored 
      the potential of HIF-1alpha and HIF-2alpha modification in BMSCs, as a tool to 
      improve cell-based angiogenic therapy. BMSCs were retrovirally transduced to 
      express stable forms of HIF-1alpha and HIF-2alpha. HIF-1alpha and, to a greater 
      extent, HIF-2alpha overexpression promoted differentiation of BMSCs to the 
      endothelial lineage, evident by CD31 and Tie-2 expression and improved adhesive 
      properties. Whereas chemotaxis toward stromal-derived factor 1 was higher in both 
      HIF-alpha-expressing BMSCs, enhanced migration toward vascular endothelial growth 
      factor was found only following overexpression of HIF-2alpha, supported by a 
      robust expression of its receptor, Flk-1. HIF-alpha expression was associated 
      with upregulation of angiogenic proteins and improved tube formation. Cytokine 
      arrays of endothelial cells stimulated by medium collected from 
      HIF-alpha-expressing BMSCs revealed further angiogenic activation and improved 
      adhesive capacity. Eventually, delivery of HIF-2alpha-transduced BMSCs induced a 
      more robust angiogenic response, compared with sham-transduced or 
      HIF-1alpha-transduced BMSCs in the corneal micropocket angiogenesis model. Our 
      results support the use of HIF-alpha genes, particularly HIF-2alpha, to augment 
      the efficacy of future cell-based therapy. Disclosure of potential conflicts of 
      interest is found at the end of this article.
FAU - Ben-Shoshan, Jeremy
AU  - Ben-Shoshan J
AD  - Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
FAU - Schwartz, Shulamit
AU  - Schwartz S
FAU - Luboshits, Galia
AU  - Luboshits G
FAU - Maysel-Auslender, Sofia
AU  - Maysel-Auslender S
FAU - Barzelay, Aya
AU  - Barzelay A
FAU - Polak-Charcon, Sylvie
AU  - Polak-Charcon S
FAU - Tzahor, Eldad
AU  - Tzahor E
FAU - Barshack, Iris
AU  - Barshack I
FAU - Barak, Adiel
AU  - Barak A
FAU - Levkovitch-Verbin, Hani
AU  - Levkovitch-Verbin H
FAU - Keren, Gad
AU  - Keren G
FAU - George, Jacob
AU  - George J
LA  - eng
PT  - Journal Article
DEP - 20080807
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Cxcr4 protein, rat)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Receptors, CXCR4)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/*metabolism
MH  - Bone Marrow Cells/*cytology/enzymology
MH  - Cell Adhesion
MH  - Cell Differentiation
MH  - Cell Movement
MH  - Cells, Cultured
MH  - Chemokine CXCL12/metabolism
MH  - Endothelial Cells/cytology/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Male
MH  - Mice
MH  - *Neovascularization, Physiologic
MH  - Paracrine Communication
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, CXCR4/metabolism
MH  - Retroviridae
MH  - Stromal Cells/cytology/enzymology/*metabolism
MH  - Transduction, Genetic
MH  - Vascular Endothelial Growth Factor A/metabolism
MH  - Vascular Endothelial Growth Factor Receptor-2/metabolism
EDAT- 2008/08/09 09:00
MHDA- 2008/12/17 09:00
CRDT- 2008/08/09 09:00
PHST- 2008/08/09 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/08/09 09:00 [entrez]
AID - 2008-0369 [pii]
AID - 10.1634/stemcells.2008-0369 [doi]
PST - ppublish
SO  - Stem Cells. 2008 Oct;26(10):2634-43. doi: 10.1634/stemcells.2008-0369. Epub 2008 
      Aug 7.