Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction

James D. Richardson, Peter J. Psaltis, Lachlan Frost, Sharon Paton, Angelo Carbone, Angela G. Bertaso, Adam J. Nelson, Dennis T L Wong, Matthew I. Worthley, Stan Gronthos, Andrew C W Zannettino, Stephen G. Worthley

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background aims: Traditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs). Methods: Three groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 × 106 cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2 and 4 weeks after MI. Results: Immediate MSC treatment attenuated early myocardial damage with EF of 35.3 ± 3.1% (dual group, n = 12) and 35.2 ± 2.2% (single group, n = 15) at 1 week after MI compared with 22.1 ± 1.9% in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 ± 3.1% by week 4, which was significantly higher than in the single-therapy group (EF 35.9 ± 1.8%, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium. Conclusions: Repeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.

LanguageEnglish
Pages460-470
Number of pages11
JournalCytotherapy
Volume16
Issue number4
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • Cardiac magnetic resonance
  • Hypoxic conditioning
  • Mesenchymal stromal cells
  • Multiple intervention
  • Myocardial infarction
  • Optimization
  • Prospective isolation
  • Repair
  • Timing

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Cancer Research
  • Transplantation

Cite this

Richardson, James D. ; Psaltis, Peter J. ; Frost, Lachlan ; Paton, Sharon ; Carbone, Angelo ; Bertaso, Angela G. ; Nelson, Adam J. ; Wong, Dennis T L ; Worthley, Matthew I. ; Gronthos, Stan ; Zannettino, Andrew C W ; Worthley, Stephen G. / Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction. In: Cytotherapy. 2014 ; Vol. 16, No. 4. pp. 460-470.
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abstract = "Background aims: Traditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs). Methods: Three groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 × 106 cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2 and 4 weeks after MI. Results: Immediate MSC treatment attenuated early myocardial damage with EF of 35.3 ± 3.1{\%} (dual group, n = 12) and 35.2 ± 2.2{\%} (single group, n = 15) at 1 week after MI compared with 22.1 ± 1.9{\%} in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 ± 3.1{\%} by week 4, which was significantly higher than in the single-therapy group (EF 35.9 ± 1.8{\%}, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium. Conclusions: Repeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.",
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Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction. / Richardson, James D.; Psaltis, Peter J.; Frost, Lachlan; Paton, Sharon; Carbone, Angelo; Bertaso, Angela G.; Nelson, Adam J.; Wong, Dennis T L; Worthley, Matthew I.; Gronthos, Stan; Zannettino, Andrew C W; Worthley, Stephen G.

In: Cytotherapy, Vol. 16, No. 4, 01.01.2014, p. 460-470.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction

AU - Richardson, James D.

AU - Psaltis, Peter J.

AU - Frost, Lachlan

AU - Paton, Sharon

AU - Carbone, Angelo

AU - Bertaso, Angela G.

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.

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KW - Cardiac magnetic resonance

KW - Hypoxic conditioning

KW - Mesenchymal stromal cells

KW - Multiple intervention

KW - Myocardial infarction

KW - Optimization

KW - Prospective isolation

KW - Repair

KW - Timing

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