Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector

Yao Liang Tang, Yi Tang, Y. Clare Zhang, Keping Qian, Leping Shen, M. Ian Phillips

Research output: Contribution to journalArticle

299 Citations (Scopus)

Abstract

OBJECTIVES: The goal of this study was to modify mesenchymal stem cells (MSCs) cells with a hypoxia-regulated heme oxygenase-1 (HO-1) plasmid to enhance the survival of MSCs in acute myocardial infarction (MI) heart. BACKGROUND: Although stem cells are being tested clinically for cardiac repair, graft cells die in the ischemic heart because of the effects of hypoxia/reoxygenation, inflammatory cytokines, and proapoptotic factors. Heme oxygenase-1 is a key component in inhibiting most of these factors. METHODS: Mesenchymal stem cells from bone marrow were transfected with either HO-1 or LacZ plasmids. Cell apoptosis was assayed in vitro after hypoxia-reoxygen treatment. In vivo, 1 × 106 of male MSCHO-1, MSCLacZ, MSCs, or medium was injected into mouse hearts 1 h after MI (n = 16/group). Cell survival was assessed in a gender-mismatched transplantation model. Apoptosis, left ventricular remodeling, and cardiac function were tested in a gender-matched model. RESULTS: In the ischemic myocardium, the MSCHO-1 group had greater expression of HO-1 and a 2-fold reduction in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling-positive cells compared with the MSCLacZ group. At seven days after implantation, the survival MSCHO-1 was five-fold greater than the MSCLacZ group; MSCHO-1 also attenuated left ventricular remodeling and enhanced the functional recovery of infarcted hearts two weeks after MI. CONCLUSIONS: A hypoxia-regulated HO-1 vector modification of MSCs enhances the tolerance of engrafted MSCs to hypoxia-reoxygen injury in vitro and improves their viability in ischemic hearts. This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.

Original languageEnglish (US)
Pages (from-to)1339-1350
Number of pages12
JournalJournal of the American College of Cardiology
Volume46
Issue number7
DOIs
StatePublished - Oct 4 2005
Externally publishedYes

Fingerprint

Heme Oxygenase-1
Mesenchymal Stromal Cells
Cell Survival
Transplants
Ventricular Remodeling
Myocardial Infarction
Plasmids
Stem Cells
Apoptosis
Cell Hypoxia
DNA Nucleotidylexotransferase
In Situ Nick-End Labeling
Myocardial Ischemia
Hypoxia
Myocardium
Transplantation
Bone Marrow
Cytokines
Wounds and Injuries
Genes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. / Tang, Yao Liang; Tang, Yi; Zhang, Y. Clare; Qian, Keping; Shen, Leping; Phillips, M. Ian.

In: Journal of the American College of Cardiology, Vol. 46, No. 7, 04.10.2005, p. 1339-1350.

Research output: Contribution to journalArticle

Tang, Yao Liang ; Tang, Yi ; Zhang, Y. Clare ; Qian, Keping ; Shen, Leping ; Phillips, M. Ian. / Improved graft mesenchymal stem cell survival in ischemic heart with a hypoxia-regulated heme oxygenase-1 vector. In: Journal of the American College of Cardiology. 2005 ; Vol. 46, No. 7. pp. 1339-1350.
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abstract = "OBJECTIVES: The goal of this study was to modify mesenchymal stem cells (MSCs) cells with a hypoxia-regulated heme oxygenase-1 (HO-1) plasmid to enhance the survival of MSCs in acute myocardial infarction (MI) heart. BACKGROUND: Although stem cells are being tested clinically for cardiac repair, graft cells die in the ischemic heart because of the effects of hypoxia/reoxygenation, inflammatory cytokines, and proapoptotic factors. Heme oxygenase-1 is a key component in inhibiting most of these factors. METHODS: Mesenchymal stem cells from bone marrow were transfected with either HO-1 or LacZ plasmids. Cell apoptosis was assayed in vitro after hypoxia-reoxygen treatment. In vivo, 1 × 106 of male MSCHO-1, MSCLacZ, MSCs, or medium was injected into mouse hearts 1 h after MI (n = 16/group). Cell survival was assessed in a gender-mismatched transplantation model. Apoptosis, left ventricular remodeling, and cardiac function were tested in a gender-matched model. RESULTS: In the ischemic myocardium, the MSCHO-1 group had greater expression of HO-1 and a 2-fold reduction in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling-positive cells compared with the MSCLacZ group. At seven days after implantation, the survival MSCHO-1 was five-fold greater than the MSCLacZ group; MSCHO-1 also attenuated left ventricular remodeling and enhanced the functional recovery of infarcted hearts two weeks after MI. CONCLUSIONS: A hypoxia-regulated HO-1 vector modification of MSCs enhances the tolerance of engrafted MSCs to hypoxia-reoxygen injury in vitro and improves their viability in ischemic hearts. This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.",
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AU - Shen, Leping

AU - Phillips, M. Ian

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