Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9

Wei Huang, Tao Wang, Dongsheng Zhang, Tiemin Zhao, Bo Dai, Atif Ashraf, Xiaohong Wang, Meifeng Xu, Ronald W. Millard, Guo Chang Fan, Muhammad Ashraf, Xi Yong Yu, Yigang Wang

Research output: Contribution to journalArticle

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Abstract

Myocardial infarction (MI) results in loss of myofibers in the ischemic zone of the heart, followed by scar formation. These factors increase barriers to mobilization of mesenchymal stem cells (MSC), thereby impeding their effectiveness in cardiac repair. This study examined MSC overexpressing CXCR4 (MSC CX4) to determine penetration into infarcted myocardium by releasing collagen degrading enzyme, matrix metalloproteinase-9 (MMP-9). In vitro, mouse MSC were utilized, including MSC using adenoviral transduction, to express CXCR4/green fluorescent protein (GFP) (MSC CX4), Null/GFP (MSC Null), MSC treated with siRNA targeting CXCR4 (MSC siR), MSC treated with control siRNA(MSC Con-siR), MSC CX4 treated with siRNA targeting MMP-9 (MSC CX4-siRMP9) and MMP-14 (MSC CX4-siRMP14), MSC derived from MMP-9 knockout mouse with adenoviral transduction for GFP (MSC MP9-), or MSC MP9- plus overexpressing CXCR4 (MSC MP9-CX4). The ability to cross the basement membrane was evaluated in all MSC using a trans-collagen gel invasion assay. The CXCR4 and MMP expression were analyzed by Western blot. In vivo, MSC with various treatments were infused into mice via tail vein injections 7 days after MI. Echocardiography was performed before harvesting hearts for analysis at 4 weeks after MSC injection. Both in vitro and in vivo studies demonstrated upregulation of MMP-9 induced by MSC CX4, promoting increased GFP + cell migration into the infarcted area in comparison to control group. This enhanced response was associated with reduced left ventricular (LV) fibrosis, increased LV free wall thickness, angiogenesis, and improved LV function. Under hypoxic conditions, MMP-9 is upregulated in MSC CX4, thus facilitating cross of the basement membrane, resulting in an improved remodeling of post-MI tissue.

Original languageEnglish (US)
Pages (from-to)778-789
Number of pages12
JournalStem Cells and Development
Volume21
Issue number5
DOIs
StatePublished - Mar 20 2012

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Matrix Metalloproteinase 9
Mesenchymal Stromal Cells
Infarction
Green Fluorescent Proteins
Small Interfering RNA
Myocardial Infarction
Basement Membrane
Injections
Collagenases
Matrix Metalloproteinases
Left Ventricular Function
Knockout Mice

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

Cite this

Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9. / Huang, Wei; Wang, Tao; Zhang, Dongsheng; Zhao, Tiemin; Dai, Bo; Ashraf, Atif; Wang, Xiaohong; Xu, Meifeng; Millard, Ronald W.; Fan, Guo Chang; Ashraf, Muhammad; Yu, Xi Yong; Wang, Yigang.

In: Stem Cells and Development, Vol. 21, No. 5, 20.03.2012, p. 778-789.

Research output: Contribution to journalArticle

Huang, W, Wang, T, Zhang, D, Zhao, T, Dai, B, Ashraf, A, Wang, X, Xu, M, Millard, RW, Fan, GC, Ashraf, M, Yu, XY & Wang, Y 2012, 'Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9', Stem Cells and Development, vol. 21, no. 5, pp. 778-789. https://doi.org/10.1089/scd.2011.0126
Huang, Wei ; Wang, Tao ; Zhang, Dongsheng ; Zhao, Tiemin ; Dai, Bo ; Ashraf, Atif ; Wang, Xiaohong ; Xu, Meifeng ; Millard, Ronald W. ; Fan, Guo Chang ; Ashraf, Muhammad ; Yu, Xi Yong ; Wang, Yigang. / Mesenchymal stem cells overexpressing CXCR4 attenuate remodeling of postmyocardial infarction by releasing matrix metalloproteinase-9. In: Stem Cells and Development. 2012 ; Vol. 21, No. 5. pp. 778-789.
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abstract = "Myocardial infarction (MI) results in loss of myofibers in the ischemic zone of the heart, followed by scar formation. These factors increase barriers to mobilization of mesenchymal stem cells (MSC), thereby impeding their effectiveness in cardiac repair. This study examined MSC overexpressing CXCR4 (MSC CX4) to determine penetration into infarcted myocardium by releasing collagen degrading enzyme, matrix metalloproteinase-9 (MMP-9). In vitro, mouse MSC were utilized, including MSC using adenoviral transduction, to express CXCR4/green fluorescent protein (GFP) (MSC CX4), Null/GFP (MSC Null), MSC treated with siRNA targeting CXCR4 (MSC siR), MSC treated with control siRNA(MSC Con-siR), MSC CX4 treated with siRNA targeting MMP-9 (MSC CX4-siRMP9) and MMP-14 (MSC CX4-siRMP14), MSC derived from MMP-9 knockout mouse with adenoviral transduction for GFP (MSC MP9-), or MSC MP9- plus overexpressing CXCR4 (MSC MP9-CX4). The ability to cross the basement membrane was evaluated in all MSC using a trans-collagen gel invasion assay. The CXCR4 and MMP expression were analyzed by Western blot. In vivo, MSC with various treatments were infused into mice via tail vein injections 7 days after MI. Echocardiography was performed before harvesting hearts for analysis at 4 weeks after MSC injection. Both in vitro and in vivo studies demonstrated upregulation of MMP-9 induced by MSC CX4, promoting increased GFP + cell migration into the infarcted area in comparison to control group. This enhanced response was associated with reduced left ventricular (LV) fibrosis, increased LV free wall thickness, angiogenesis, and improved LV function. Under hypoxic conditions, MMP-9 is upregulated in MSC CX4, thus facilitating cross of the basement membrane, resulting in an improved remodeling of post-MI tissue.",
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AU - Ashraf, Atif

AU - Wang, Xiaohong

AU - Xu, Meifeng

AU - Millard, Ronald W.

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AU - Ashraf, Muhammad

AU - Yu, Xi Yong

AU - Wang, Yigang

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