Abstract
We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1α. Rat bone marrow-derived MSCs were used as nontransduced (MSCs) or transduced with adenoviral-null vector (MSCs) or vector encoding for IGF-1 (MSCs). MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus MSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3β besides release of SDF-1α in parallel with IGF-1 expression in MSCs. For in vivo studies, 70 μL of DMEM without cells (group 1) or containing 1.5×10MSCs (group 2) or MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of MSCs (P<0.06 versus MSCs) (n=6 per group). SDF-1α was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit, MDR1, CD31, and CD34 cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P<0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1α signaling and culminated in extensive angiomyogenesis in the infarcted heart.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1300-1308 |
| Number of pages | 9 |
| Journal | Circulation research |
| Volume | 103 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 21 2008 |
| Externally published | Yes |
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Keywords
- Heart
- IGF-1
- Myocardial infarction
- SDF-1
- Stem cells
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1α/CXCR4 signaling to promote myocardial repair. / Haider, Husnain Kh; Jiang, Shujia; Idris, Niagara M.; Ashraf, Muhammad.
In: Circulation research, Vol. 103, No. 11, 21.11.2008, p. 1300-1308.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1α/CXCR4 signaling to promote myocardial repair
AU - Haider, Husnain Kh
AU - Jiang, Shujia
AU - Idris, Niagara M.
AU - Ashraf, Muhammad
PY - 2008/11/21
Y1 - 2008/11/21
N2 - We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1α. Rat bone marrow-derived MSCs were used as nontransduced (MSCs) or transduced with adenoviral-null vector (MSCs) or vector encoding for IGF-1 (MSCs). MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus MSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3β besides release of SDF-1α in parallel with IGF-1 expression in MSCs. For in vivo studies, 70 μL of DMEM without cells (group 1) or containing 1.5×10MSCs (group 2) or MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of MSCs (P<0.06 versus MSCs) (n=6 per group). SDF-1α was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit, MDR1, CD31, and CD34 cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P<0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1α signaling and culminated in extensive angiomyogenesis in the infarcted heart.
AB - We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1α. Rat bone marrow-derived MSCs were used as nontransduced (MSCs) or transduced with adenoviral-null vector (MSCs) or vector encoding for IGF-1 (MSCs). MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus MSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3β besides release of SDF-1α in parallel with IGF-1 expression in MSCs. For in vivo studies, 70 μL of DMEM without cells (group 1) or containing 1.5×10MSCs (group 2) or MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of MSCs (P<0.06 versus MSCs) (n=6 per group). SDF-1α was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit, MDR1, CD31, and CD34 cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P<0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1α signaling and culminated in extensive angiomyogenesis in the infarcted heart.
KW - Heart
KW - IGF-1
KW - Myocardial infarction
KW - SDF-1
KW - Stem cells
UR - http://www.scopus.com/inward/record.url?scp=58149345104&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58149345104&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.108.186742
DO - 10.1161/CIRCRESAHA.108.186742
M3 - Article
VL - 103
SP - 1300
EP - 1308
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 11
ER -