Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction

Adam R. Williams, Konstantinos E. Hatzistergos, Benjamin Addicott, Fred McCall, Decio Carvalho, Viky Suncion, Azorides R Morales, Jose Da Silva, Mark A. Sussman, Alan W. Heldman, Joshua Hare

Research output: Contribution to journalArticle

273 Citations (Scopus)

Abstract

BACKGROUND - : Because mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h) MSCs with c-kit hCSCs produces greater infarct size reduction compared with either cell administered alone after myocardial infarction (MI). METHODS AND RESULTS - : Yorkshire swine underwent balloon occlusion of the left anterior descending coronary artery followed by reperfusion and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial combination hCSCs/hMSCs (1 million cells/200 million cells, n=5), hCSCs alone (1 million cells, n=5), hMSCs alone (200 million cells, n=5), or placebo (phosphate-buffered saline; n=5) was injected into the infarct border zones at 14 days after MI. Phenotypic response to cell therapy was assessed by cardiac magnetic resonance imaging and micromanometer conductance catheterization hemodynamics. Although each cell therapy group had reduced MI size relative to placebo (P<0.05), the MI size reduction was 2-fold greater in combination versus either cell therapy alone (P<0.05). Accompanying enhanced MI size reduction were substantial improvement in left ventricular chamber compliance (end-diastolic pressure-volume relationship; P<0.01) and contractility (preload recruitable stroke work and dP/dtmax; P<0.05) in combination-treated swine. Ejection fraction was restored to baseline in cell-treated pigs, whereas placebo pigs had persistently depressed left ventricular function (P<0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group versus either cell type alone (P<0.001). CONCLUSIONS - : Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction and restores diastolic and systolic function toward normal after MI. Taken together, these findings illustrate important biological interactions between c-kit CSCs and MSCs that enhance cell-based therapeutic responses.

Original languageEnglish
Pages (from-to)213-223
Number of pages11
JournalCirculation
Volume127
Issue number2
DOIs
StatePublished - Jan 15 2013

Fingerprint

Mesenchymal Stromal Cells
Stem Cells
Bone Marrow
Myocardial Infarction
Swine
Cell- and Tissue-Based Therapy
Placebos
Balloon Occlusion
Methylprednisolone
Group Psychotherapy
Left Ventricular Function
Catheterization
Cyclosporine
Compliance
Reperfusion
Cicatrix
Cell Differentiation
Coronary Vessels
Hemodynamics
Immunohistochemistry

Keywords

  • heart failure
  • mesenchymal stem cells
  • myocardial infarction
  • stem cells

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. / Williams, Adam R.; Hatzistergos, Konstantinos E.; Addicott, Benjamin; McCall, Fred; Carvalho, Decio; Suncion, Viky; Morales, Azorides R; Da Silva, Jose; Sussman, Mark A.; Heldman, Alan W.; Hare, Joshua.

In: Circulation, Vol. 127, No. 2, 15.01.2013, p. 213-223.

Research output: Contribution to journalArticle

Williams, AR, Hatzistergos, KE, Addicott, B, McCall, F, Carvalho, D, Suncion, V, Morales, AR, Da Silva, J, Sussman, MA, Heldman, AW & Hare, J 2013, 'Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction', Circulation, vol. 127, no. 2, pp. 213-223. https://doi.org/10.1161/CIRCULATIONAHA.112.131110
Williams, Adam R. ; Hatzistergos, Konstantinos E. ; Addicott, Benjamin ; McCall, Fred ; Carvalho, Decio ; Suncion, Viky ; Morales, Azorides R ; Da Silva, Jose ; Sussman, Mark A. ; Heldman, Alan W. ; Hare, Joshua. / Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. In: Circulation. 2013 ; Vol. 127, No. 2. pp. 213-223.
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AU - McCall, Fred

AU - Carvalho, Decio

AU - Suncion, Viky

AU - Morales, Azorides R

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