Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure

Anaïs Kervadec*, Valérie Bellamy, Nadia El Harane, Lousineh Arakélian, Valérie Vanneaux, Isabelle Cacciapuoti, Hany Nemetalla, Marie Cécile Périer, Hadi Daood Toeg, Adèle Richart, Mathilde Lemitre, Min Yin, Xavier Loyer, Jérôme Larghero, Albert Hagège, Marc Ruel, Chantal M. Boulanger, Jean Sébastien Silvestre, Philippe Menasché, Nisa K.E. Renault

*Corresponding author for this work

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Background Cell-based therapies are being explored as a therapeutic option for patients with chronic heart failure following myocardial infarction. Extracellular vesicles (EV), including exosomes and microparticles, secreted by transplanted cells may orchestrate their paracrine therapeutic effects. We assessed whether post-infarction administration of EV released by human embryonic stem cell-derived cardiovascular progenitors (hESC-Pg) can provide equivalent benefits to administered hESC-Pg and whether hESC-Pg and EV treatments activate similar endogenous pathways. Methods Mice underwent surgical occlusion of their left coronary arteries. After 2-3 weeks, 95 mice included in the study were treated with hESC-Pg, EV, or Minimal Essential Medium Alpha Medium (alpha-MEM; vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. functional and histologic end-points were blindly assessed 6 weeks later, and hearts were processed for gene profiling. Genes differentially expressed between control hearts and hESC-Pg-treated and EV-treated hearts were clustered into functionally relevant pathways. Results At 6 weeks after hESC-Pg administration, treated mice had significantly reduced left ventricular end-systolic (-4.20 ± 0.96 μl or -7.5%, p = 0.0007) and end-diastolic (-4.48 ± 1.47 μl or -4.4%, p = 0.009) volumes compared with baseline values despite the absence of any transplanted hESC-Pg or human embryonic stem cell-derived cardiomyocytes in the treated mouse hearts. Equal benefits were seen with the injection of hESC-Pg-derived EV, whereas animals injected with alpha-MEM (vehicle control) did not improve significantly. Histologic examination suggested a slight reduction in infarct size in hESC-Pg-treated animals and EV-treated animals compared with alpha-MEM-treated control animals. In the hESC-Pg-treated and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated compared with the control group. Among the 49 enriched pathways associated with these up-regulated genes that could be related to cardiac function or regeneration, 78% were predicted to improve cardiac function through increased cell survival and/or proliferation or DNA repair as well as pathways related to decreased fibrosis and heart failure. Conclusions In this post-infarct heart failure model, either hESC-Pg or their secreted EV enhance recovery of cardiac function and similarly affect cardiac gene expression patterns that could be related to this recovery. Although the mechanisms by which EV improve cardiac function remain to be determined, these results support the idea that a paracrine mechanism is sufficient to effect functional recovery in cell-based therapies for post-infarction-related chronic heart failure.

Original languageEnglish (US)
Pages (from-to)795-807
Number of pages13
JournalJournal of Heart and Lung Transplantation
Volume35
Issue number6
DOIs
StatePublished - Jun 1 2016

Fingerprint

Heart Failure
Therapeutics
Cell- and Tissue-Based Therapy
Infarction
Genes
Extracellular Vesicles
Human Embryonic Stem Cells
Exosomes
Pseudogenes
Injections
Recovery of Function
Therapeutic Uses
Cardiac Myocytes
DNA Repair
Regeneration
Cell Survival
Coronary Vessels
Myocardium
Fibrosis
Myocardial Infarction

Keywords

  • cardiovascular progenitor cells
  • cell therapy
  • embryonic stem cells
  • exosomes
  • extracellular vesicles
  • heart failure
  • microparticles

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Kervadec, Anaïs ; Bellamy, Valérie ; El Harane, Nadia ; Arakélian, Lousineh ; Vanneaux, Valérie ; Cacciapuoti, Isabelle ; Nemetalla, Hany ; Périer, Marie Cécile ; Toeg, Hadi Daood ; Richart, Adèle ; Lemitre, Mathilde ; Yin, Min ; Loyer, Xavier ; Larghero, Jérôme ; Hagège, Albert ; Ruel, Marc ; Boulanger, Chantal M. ; Silvestre, Jean Sébastien ; Menasché, Philippe ; Renault, Nisa K.E. / Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. In: Journal of Heart and Lung Transplantation. 2016 ; Vol. 35, No. 6. pp. 795-807.
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title = "Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure",
abstract = "Background Cell-based therapies are being explored as a therapeutic option for patients with chronic heart failure following myocardial infarction. Extracellular vesicles (EV), including exosomes and microparticles, secreted by transplanted cells may orchestrate their paracrine therapeutic effects. We assessed whether post-infarction administration of EV released by human embryonic stem cell-derived cardiovascular progenitors (hESC-Pg) can provide equivalent benefits to administered hESC-Pg and whether hESC-Pg and EV treatments activate similar endogenous pathways. Methods Mice underwent surgical occlusion of their left coronary arteries. After 2-3 weeks, 95 mice included in the study were treated with hESC-Pg, EV, or Minimal Essential Medium Alpha Medium (alpha-MEM; vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. functional and histologic end-points were blindly assessed 6 weeks later, and hearts were processed for gene profiling. Genes differentially expressed between control hearts and hESC-Pg-treated and EV-treated hearts were clustered into functionally relevant pathways. Results At 6 weeks after hESC-Pg administration, treated mice had significantly reduced left ventricular end-systolic (-4.20 ± 0.96 μl or -7.5{\%}, p = 0.0007) and end-diastolic (-4.48 ± 1.47 μl or -4.4{\%}, p = 0.009) volumes compared with baseline values despite the absence of any transplanted hESC-Pg or human embryonic stem cell-derived cardiomyocytes in the treated mouse hearts. Equal benefits were seen with the injection of hESC-Pg-derived EV, whereas animals injected with alpha-MEM (vehicle control) did not improve significantly. Histologic examination suggested a slight reduction in infarct size in hESC-Pg-treated animals and EV-treated animals compared with alpha-MEM-treated control animals. In the hESC-Pg-treated and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated compared with the control group. Among the 49 enriched pathways associated with these up-regulated genes that could be related to cardiac function or regeneration, 78{\%} were predicted to improve cardiac function through increased cell survival and/or proliferation or DNA repair as well as pathways related to decreased fibrosis and heart failure. Conclusions In this post-infarct heart failure model, either hESC-Pg or their secreted EV enhance recovery of cardiac function and similarly affect cardiac gene expression patterns that could be related to this recovery. Although the mechanisms by which EV improve cardiac function remain to be determined, these results support the idea that a paracrine mechanism is sufficient to effect functional recovery in cell-based therapies for post-infarction-related chronic heart failure.",
keywords = "cardiovascular progenitor cells, cell therapy, embryonic stem cells, exosomes, extracellular vesicles, heart failure, microparticles",
author = "Ana{\"i}s Kervadec and Val{\'e}rie Bellamy and {El Harane}, Nadia and Lousineh Arak{\'e}lian and Val{\'e}rie Vanneaux and Isabelle Cacciapuoti and Hany Nemetalla and P{\'e}rier, {Marie C{\'e}cile} and Toeg, {Hadi Daood} and Ad{\`e}le Richart and Mathilde Lemitre and Min Yin and Xavier Loyer and J{\'e}r{\^o}me Larghero and Albert Hag{\`e}ge and Marc Ruel and Boulanger, {Chantal M.} and Silvestre, {Jean S{\'e}bastien} and Philippe Menasch{\'e} and Renault, {Nisa K.E.}",
year = "2016",
month = "6",
day = "1",
doi = "10.1016/j.healun.2016.01.013",
language = "English (US)",
volume = "35",
pages = "795--807",
journal = "Journal of Heart and Lung Transplantation",
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Kervadec, A, Bellamy, V, El Harane, N, Arakélian, L, Vanneaux, V, Cacciapuoti, I, Nemetalla, H, Périer, MC, Toeg, HD, Richart, A, Lemitre, M, Yin, M, Loyer, X, Larghero, J, Hagège, A, Ruel, M, Boulanger, CM, Silvestre, JS, Menasché, P & Renault, NKE 2016, 'Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure', Journal of Heart and Lung Transplantation, vol. 35, no. 6, pp. 795-807. https://doi.org/10.1016/j.healun.2016.01.013

Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. / Kervadec, Anaïs; Bellamy, Valérie; El Harane, Nadia; Arakélian, Lousineh; Vanneaux, Valérie; Cacciapuoti, Isabelle; Nemetalla, Hany; Périer, Marie Cécile; Toeg, Hadi Daood; Richart, Adèle; Lemitre, Mathilde; Yin, Min; Loyer, Xavier; Larghero, Jérôme; Hagège, Albert; Ruel, Marc; Boulanger, Chantal M.; Silvestre, Jean Sébastien; Menasché, Philippe; Renault, Nisa K.E.

In: Journal of Heart and Lung Transplantation, Vol. 35, No. 6, 01.06.2016, p. 795-807.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure

AU - Kervadec, Anaïs

AU - Bellamy, Valérie

AU - El Harane, Nadia

AU - Arakélian, Lousineh

AU - Vanneaux, Valérie

AU - Cacciapuoti, Isabelle

AU - Nemetalla, Hany

AU - Périer, Marie Cécile

AU - Toeg, Hadi Daood

AU - Richart, Adèle

AU - Lemitre, Mathilde

AU - Yin, Min

AU - Loyer, Xavier

AU - Larghero, Jérôme

AU - Hagège, Albert

AU - Ruel, Marc

AU - Boulanger, Chantal M.

AU - Silvestre, Jean Sébastien

AU - Menasché, Philippe

AU - Renault, Nisa K.E.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Background Cell-based therapies are being explored as a therapeutic option for patients with chronic heart failure following myocardial infarction. Extracellular vesicles (EV), including exosomes and microparticles, secreted by transplanted cells may orchestrate their paracrine therapeutic effects. We assessed whether post-infarction administration of EV released by human embryonic stem cell-derived cardiovascular progenitors (hESC-Pg) can provide equivalent benefits to administered hESC-Pg and whether hESC-Pg and EV treatments activate similar endogenous pathways. Methods Mice underwent surgical occlusion of their left coronary arteries. After 2-3 weeks, 95 mice included in the study were treated with hESC-Pg, EV, or Minimal Essential Medium Alpha Medium (alpha-MEM; vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. functional and histologic end-points were blindly assessed 6 weeks later, and hearts were processed for gene profiling. Genes differentially expressed between control hearts and hESC-Pg-treated and EV-treated hearts were clustered into functionally relevant pathways. Results At 6 weeks after hESC-Pg administration, treated mice had significantly reduced left ventricular end-systolic (-4.20 ± 0.96 μl or -7.5%, p = 0.0007) and end-diastolic (-4.48 ± 1.47 μl or -4.4%, p = 0.009) volumes compared with baseline values despite the absence of any transplanted hESC-Pg or human embryonic stem cell-derived cardiomyocytes in the treated mouse hearts. Equal benefits were seen with the injection of hESC-Pg-derived EV, whereas animals injected with alpha-MEM (vehicle control) did not improve significantly. Histologic examination suggested a slight reduction in infarct size in hESC-Pg-treated animals and EV-treated animals compared with alpha-MEM-treated control animals. In the hESC-Pg-treated and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated compared with the control group. Among the 49 enriched pathways associated with these up-regulated genes that could be related to cardiac function or regeneration, 78% were predicted to improve cardiac function through increased cell survival and/or proliferation or DNA repair as well as pathways related to decreased fibrosis and heart failure. Conclusions In this post-infarct heart failure model, either hESC-Pg or their secreted EV enhance recovery of cardiac function and similarly affect cardiac gene expression patterns that could be related to this recovery. Although the mechanisms by which EV improve cardiac function remain to be determined, these results support the idea that a paracrine mechanism is sufficient to effect functional recovery in cell-based therapies for post-infarction-related chronic heart failure.

AB - Background Cell-based therapies are being explored as a therapeutic option for patients with chronic heart failure following myocardial infarction. Extracellular vesicles (EV), including exosomes and microparticles, secreted by transplanted cells may orchestrate their paracrine therapeutic effects. We assessed whether post-infarction administration of EV released by human embryonic stem cell-derived cardiovascular progenitors (hESC-Pg) can provide equivalent benefits to administered hESC-Pg and whether hESC-Pg and EV treatments activate similar endogenous pathways. Methods Mice underwent surgical occlusion of their left coronary arteries. After 2-3 weeks, 95 mice included in the study were treated with hESC-Pg, EV, or Minimal Essential Medium Alpha Medium (alpha-MEM; vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. functional and histologic end-points were blindly assessed 6 weeks later, and hearts were processed for gene profiling. Genes differentially expressed between control hearts and hESC-Pg-treated and EV-treated hearts were clustered into functionally relevant pathways. Results At 6 weeks after hESC-Pg administration, treated mice had significantly reduced left ventricular end-systolic (-4.20 ± 0.96 μl or -7.5%, p = 0.0007) and end-diastolic (-4.48 ± 1.47 μl or -4.4%, p = 0.009) volumes compared with baseline values despite the absence of any transplanted hESC-Pg or human embryonic stem cell-derived cardiomyocytes in the treated mouse hearts. Equal benefits were seen with the injection of hESC-Pg-derived EV, whereas animals injected with alpha-MEM (vehicle control) did not improve significantly. Histologic examination suggested a slight reduction in infarct size in hESC-Pg-treated animals and EV-treated animals compared with alpha-MEM-treated control animals. In the hESC-Pg-treated and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated compared with the control group. Among the 49 enriched pathways associated with these up-regulated genes that could be related to cardiac function or regeneration, 78% were predicted to improve cardiac function through increased cell survival and/or proliferation or DNA repair as well as pathways related to decreased fibrosis and heart failure. Conclusions In this post-infarct heart failure model, either hESC-Pg or their secreted EV enhance recovery of cardiac function and similarly affect cardiac gene expression patterns that could be related to this recovery. Although the mechanisms by which EV improve cardiac function remain to be determined, these results support the idea that a paracrine mechanism is sufficient to effect functional recovery in cell-based therapies for post-infarction-related chronic heart failure.

KW - cardiovascular progenitor cells

KW - cell therapy

KW - embryonic stem cells

KW - exosomes

KW - extracellular vesicles

KW - heart failure

KW - microparticles

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