Repeated transplantation of allogeneic cardiosphere-derived cells boosts therapeutic benefits without immune sensitization in a rat model of myocardial infarction

Heidi Reich, Eleni Tseliou, Geoffrey de Couto, David Angert, Jackelyn Valle, Yuzu Kubota, Daniel Luthringer, James Mirocha, Baiming Sun, Rachel R. Smith, Linda Marbán, Eduardo Marbán

Research output: Contribution to journalArticle

Abstract

Background A single dose of allogeneic cardiosphere-derived cells (CDCs) improves cardiac function and reduces scarring, and increases viable myocardium in the infarcted rat and pig heart without eliciting a detrimental immune response. Clinical trials using single doses of allogeneic human CDCs are underway. It is unknown whether repeat dosing confers additional benefit or if it elicits an immune response. Methods Wistar–Kyoto rats underwent coronary artery ligation and intramyocardial injection of CDCs, with a second thoracotomy and repeat CDC injection 3 weeks later. Treatment permutations included 2 doses of allogeneic Brown–Norway CDCs (n = 24), syngeneic Wistar–Kyoto CDCs (n = 24), xenogeneic human CDCs (n = 24) or saline (n = 8). Cardiac function was assessed by transthoracic echocardiography, infarct size and inflammatory infiltration by histology, and cellular and humoral immune responses by lymphocyte proliferation and alloantibody assays. Results Repeat dosing of allogeneic and syngeneic CDCs improved ejection fraction by 5.2% (95% CI 2.1 to 8.3) and 6.8% (95% CI 3.8 to 9.8) after the first dose, and by 3.4% (95% CI 0.1% to 6.8%) and 6.4% (95% CI 4.2% to 8.6%) after the second dose. Infarct size was equally reduced with repeat dosing of syngeneic and allogeneic CDCs relative to xenogeneic and control treatments (p < 0.0001). Significant rejection-like infiltrates were present only in the xenogeneic group; likewise, lymphocyte proliferation and antibody assays were positive in the xenogeneic and negative in syngeneic and allogeneic groups. Conclusions Repeat dosing of allogeneic CDCs in immunocompetent rats is safe and effective, consistent with the known immunomodulatory and anti-inflammatory properties of CDCs. These findings motivate clinical testing of repeatedly dosed CDCs for chronic heart disease.

Original languageEnglish (US)
Pages (from-to)1348-1357
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume35
Issue number11
DOIs
StatePublished - Nov 1 2016
Externally publishedYes

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Homologous Transplantation
Myocardial Infarction
Therapeutics
Lymphocytes
Isoantibodies
Injections
Thoracotomy
Humoral Immunity
Cellular Immunity
Cicatrix
Ligation
Echocardiography
Heart Diseases
Coronary Vessels
Myocardium
Histology
Chronic Disease
Anti-Inflammatory Agents
Swine
Clinical Trials

Keywords

  • cardiosphere-derived cells
  • cell therapy
  • regenerative medicine
  • regneration
  • stem cells

ASJC Scopus subject areas

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

Cite this

Repeated transplantation of allogeneic cardiosphere-derived cells boosts therapeutic benefits without immune sensitization in a rat model of myocardial infarction. / Reich, Heidi; Tseliou, Eleni; de Couto, Geoffrey; Angert, David; Valle, Jackelyn; Kubota, Yuzu; Luthringer, Daniel; Mirocha, James; Sun, Baiming; Smith, Rachel R.; Marbán, Linda; Marbán, Eduardo.

In: Journal of Heart and Lung Transplantation, Vol. 35, No. 11, 01.11.2016, p. 1348-1357.

Research output: Contribution to journalArticle

Reich, H, Tseliou, E, de Couto, G, Angert, D, Valle, J, Kubota, Y, Luthringer, D, Mirocha, J, Sun, B, Smith, RR, Marbán, L & Marbán, E 2016, 'Repeated transplantation of allogeneic cardiosphere-derived cells boosts therapeutic benefits without immune sensitization in a rat model of myocardial infarction', Journal of Heart and Lung Transplantation, vol. 35, no. 11, pp. 1348-1357. https://doi.org/10.1016/j.healun.2016.05.008
Reich, Heidi ; Tseliou, Eleni ; de Couto, Geoffrey ; Angert, David ; Valle, Jackelyn ; Kubota, Yuzu ; Luthringer, Daniel ; Mirocha, James ; Sun, Baiming ; Smith, Rachel R. ; Marbán, Linda ; Marbán, Eduardo. / Repeated transplantation of allogeneic cardiosphere-derived cells boosts therapeutic benefits without immune sensitization in a rat model of myocardial infarction. In: Journal of Heart and Lung Transplantation. 2016 ; Vol. 35, No. 11. pp. 1348-1357.
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AU - Angert, David

AU - Valle, Jackelyn

AU - Kubota, Yuzu

AU - Luthringer, Daniel

AU - Mirocha, James

AU - Sun, Baiming

AU - Smith, Rachel R.

AU - Marbán, Linda

AU - Marbán, Eduardo

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N2 - Background A single dose of allogeneic cardiosphere-derived cells (CDCs) improves cardiac function and reduces scarring, and increases viable myocardium in the infarcted rat and pig heart without eliciting a detrimental immune response. Clinical trials using single doses of allogeneic human CDCs are underway. It is unknown whether repeat dosing confers additional benefit or if it elicits an immune response. Methods Wistar–Kyoto rats underwent coronary artery ligation and intramyocardial injection of CDCs, with a second thoracotomy and repeat CDC injection 3 weeks later. Treatment permutations included 2 doses of allogeneic Brown–Norway CDCs (n = 24), syngeneic Wistar–Kyoto CDCs (n = 24), xenogeneic human CDCs (n = 24) or saline (n = 8). Cardiac function was assessed by transthoracic echocardiography, infarct size and inflammatory infiltration by histology, and cellular and humoral immune responses by lymphocyte proliferation and alloantibody assays. Results Repeat dosing of allogeneic and syngeneic CDCs improved ejection fraction by 5.2% (95% CI 2.1 to 8.3) and 6.8% (95% CI 3.8 to 9.8) after the first dose, and by 3.4% (95% CI 0.1% to 6.8%) and 6.4% (95% CI 4.2% to 8.6%) after the second dose. Infarct size was equally reduced with repeat dosing of syngeneic and allogeneic CDCs relative to xenogeneic and control treatments (p < 0.0001). Significant rejection-like infiltrates were present only in the xenogeneic group; likewise, lymphocyte proliferation and antibody assays were positive in the xenogeneic and negative in syngeneic and allogeneic groups. Conclusions Repeat dosing of allogeneic CDCs in immunocompetent rats is safe and effective, consistent with the known immunomodulatory and anti-inflammatory properties of CDCs. These findings motivate clinical testing of repeatedly dosed CDCs for chronic heart disease.

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