TY - JOUR
T1 - Impact of timing and dose of mesenchymal stromal cell therapy in a preclinical model of acute myocardial infarction
AU - Richardson, James D.
AU - Bertaso, Angela G.
AU - Psaltis, Peter J.
AU - Frost, Lachlan
AU - Carbone, Angelo
AU - Paton, Sharon
AU - Nelson, Adam J.
AU - Wong, Dennis T L
AU - Worthley, Matthew I.
AU - Gronthos, Stan
AU - Zannettino, Andrew C W
AU - Worthley, Stephen G.
N1 - Funding Information:
The authors thank Mr Tom Sullivan (University of Adelaide) for support with statistics and Dr Stephen Fitter (University of Adelaide) for assistance with the GFP retroviral transduction. J.D.R. is supported by an International Postgraduate Research Scholarship at the University of Adelaide, Australia. P.J.P. has received funding from the National Health and Medical Research Council of Australia and the Royal Australasian College of Physicians. D.W. is supported by the National Health and Medical Research Council and Australian National Heart Foundation postgraduate scholarship.
PY - 2013
Y1 - 2013
N2 - Background: Although mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI. Methods and Results: Sprague-Dawley rats were used. Allogeneic prospectively isolated MSC ("low" dose 1 × 106 or "high" dose 2 × 106 cells) were delivered by transepicardial injection immediately after MI ("early-low," "early-high"), or 1 week later ("late-low," "late-high"). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 ± 1.7%, early-low 26.5 ± 3.2%, early-high 7.9 ± 2.6%, late-low 19.6 ± 3.5%, late-high 17.9 ± 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration. Conclusions: The nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients.
AB - Background: Although mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI. Methods and Results: Sprague-Dawley rats were used. Allogeneic prospectively isolated MSC ("low" dose 1 × 106 or "high" dose 2 × 106 cells) were delivered by transepicardial injection immediately after MI ("early-low," "early-high"), or 1 week later ("late-low," "late-high"). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 ± 1.7%, early-low 26.5 ± 3.2%, early-high 7.9 ± 2.6%, late-low 19.6 ± 3.5%, late-high 17.9 ± 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration. Conclusions: The nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients.
KW - Mesenchymal stem cells
KW - cardiac magnetic resonance
KW - hypoxic conditioning
KW - myocardial infarction
KW - optimisation
KW - prospective isolation
KW - repair
KW - timing
UR - http://www.scopus.com/inward/record.url?scp=84879805933&partnerID=8YFLogxK
U2 - 10.1016/j.cardfail.2013.03.011
DO - 10.1016/j.cardfail.2013.03.011
M3 - Article
C2 - 23663817
AN - SCOPUS:84879805933
VL - 19
SP - 342
EP - 353
JO - Journal of Cardiac Failure
JF - Journal of Cardiac Failure
SN - 1071-9164
IS - 5
ER -