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 language | English |
|---|---|
| Pages (from-to) | 213-223 |
| Number of pages | 11 |
| Journal | Circulation |
| Volume | 127 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 15 2013 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - 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
AU - Williams, Adam R.
AU - Hatzistergos, Konstantinos E.
AU - Addicott, Benjamin
AU - McCall, Fred
AU - Carvalho, Decio
AU - Suncion, Viky
AU - Morales, Azorides R
AU - Da Silva, Jose
AU - Sussman, Mark A.
AU - Heldman, Alan W.
AU - Hare, Joshua
PY - 2013/1/15
Y1 - 2013/1/15
N2 - 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.
AB - 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.
KW - heart failure
KW - mesenchymal stem cells
KW - myocardial infarction
KW - stem cells
UR - http://www.scopus.com/inward/record.url?scp=84872281137&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872281137&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.112.131110
DO - 10.1161/CIRCULATIONAHA.112.131110
M3 - Article
C2 - 23224061
AN - SCOPUS:84872281137
VL - 127
SP - 213
EP - 223
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 2
ER -