Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction

Geoffrey De Couto, Weixin Liu, Eleni Tseliou, Baiming Sun, Nupur Makkar, Hideaki Kanazawa, Moshe Arditi, Eduardo Marbán

Research output: Contribution to journalArticle

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Abstract

Ischemic injury in the heart induces an inflammatory cascade that both repairs damage and exacerbates scar tissue formation. Cardiosphere-derived cells (CDCs) are a stem-like population that is derived ex vivo from cardiac biopsies; they confer both cardioprotection and regeneration in acute myocardial infarction (MI). While the regenerative effects of CDCs in chronic settings have been studied extensively, little is known about how CDCs confer the cardioprotective process known as cellular postconditioning. Here, we used an in vivo rat model of ischemia/reperfusion (IR) injury-induced MI and in vitro coculture assays to investigate how CDCs protect stressed cardiomyocytes. Compared with control animals, animals that received CDCs 20 minutes after IR had reduced infarct size when measured at 48 hours. CDCs modified the myocardial leukocyte population after ischemic injury. Specifically, introduction of CDCs reduced the number of CD68+ macrophages, and these CDCs secreted factors that polarized macrophages toward a distinctive cardioprotective phenotype that was not M1 or M2. Systemic depletion of macrophages with clodronate abolished CDC-mediated cardioprotection. Using both in vitro coculture assays and a rat model of adoptive transfer after IR, we determined that CDC-conditioned macrophages attenuated cardiomyocyte apoptosis and reduced infarct size, thereby recapitulating the beneficial effects of CDC therapy. Together, our data indicate that CDCs limit acute injury by polarizing an effector macrophage population within the heart.

Original languageEnglish
Pages (from-to)3147-3162
Number of pages16
JournalJournal of Clinical Investigation
Volume125
Issue number8
DOIs
Publication statusPublished - 2015 Jan 1

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Macrophages
Myocardial Infarction
Coculture Techniques
Cardiac Myocytes
Reperfusion
Ischemia
Heart Injuries
Clodronic Acid
Population
Adoptive Transfer
Wounds and Injuries
Cell- and Tissue-Based Therapy
Reperfusion Injury
Cicatrix
Regeneration
Leukocytes
Stem Cells
Cell Count
Apoptosis
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

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Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. / De Couto, Geoffrey; Liu, Weixin; Tseliou, Eleni; Sun, Baiming; Makkar, Nupur; Kanazawa, Hideaki; Arditi, Moshe; Marbán, Eduardo.

In: Journal of Clinical Investigation, Vol. 125, No. 8, 01.01.2015, p. 3147-3162.

Research output: Contribution to journalArticle

De Couto, G, Liu, W, Tseliou, E, Sun, B, Makkar, N, Kanazawa, H, Arditi, M & Marbán, E 2015, 'Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction', Journal of Clinical Investigation, vol. 125, no. 8, pp. 3147-3162. https://doi.org/10.1172/JCI81321
De Couto, Geoffrey ; Liu, Weixin ; Tseliou, Eleni ; Sun, Baiming ; Makkar, Nupur ; Kanazawa, Hideaki ; Arditi, Moshe ; Marbán, Eduardo. / Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 8. pp. 3147-3162.
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