Formation of large coronary arteries by cardiac progenitor cells

Jochen Tillmanns, Marcello Rota, Toru Hosoda, Yu Misao, Grazia Esposito, Arantxa Gonzalez, Serena Vitale, Carola Parolin, Saori Yasuzawa-Amano, John Muraski, Antonella De Angelis, Nicole LeCapitaine, Robert W. Siggins, Maria Loredo, Claudia Bearzi, Roberto Bolli, Konrad Urbanek, Annarosa Leri, Jan Kajstura, Piero Anversa

Research output: Contribution to journalArticle

Abstract

Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1α, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.

Original languageEnglish (US)
Pages (from-to)1668-1673
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number5
DOIs
StatePublished - Feb 5 2008
Externally publishedYes

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Coronary Vessels
Stem Cells
Myocardium
Blood Vessels
Coronary Artery Disease
Capillary Resistance
Hypoxia-Inducible Factor 1
Coronary Circulation
Western World
Hepatocyte Growth Factor
Arterioles
Somatomedins
Muscular Diseases
Cardiac Myocytes
Smooth Muscle Myocytes
Regeneration
Up-Regulation
Endothelial Cells
Heart Failure
Injections

Keywords

  • Coronary blood flow
  • Infarct size
  • Myocardial regeneration
  • Stem cells
  • Vasculogenesis

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Tillmanns, J., Rota, M., Hosoda, T., Misao, Y., Esposito, G., Gonzalez, A., ... Anversa, P. (2008). Formation of large coronary arteries by cardiac progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 105(5), 1668-1673. https://doi.org/10.1073/pnas.0706315105

Formation of large coronary arteries by cardiac progenitor cells. / Tillmanns, Jochen; Rota, Marcello; Hosoda, Toru; Misao, Yu; Esposito, Grazia; Gonzalez, Arantxa; Vitale, Serena; Parolin, Carola; Yasuzawa-Amano, Saori; Muraski, John; De Angelis, Antonella; LeCapitaine, Nicole; Siggins, Robert W.; Loredo, Maria; Bearzi, Claudia; Bolli, Roberto; Urbanek, Konrad; Leri, Annarosa; Kajstura, Jan; Anversa, Piero.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 5, 05.02.2008, p. 1668-1673.

Research output: Contribution to journalArticle

Tillmanns, J, Rota, M, Hosoda, T, Misao, Y, Esposito, G, Gonzalez, A, Vitale, S, Parolin, C, Yasuzawa-Amano, S, Muraski, J, De Angelis, A, LeCapitaine, N, Siggins, RW, Loredo, M, Bearzi, C, Bolli, R, Urbanek, K, Leri, A, Kajstura, J & Anversa, P 2008, 'Formation of large coronary arteries by cardiac progenitor cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 5, pp. 1668-1673. https://doi.org/10.1073/pnas.0706315105
Tillmanns, Jochen ; Rota, Marcello ; Hosoda, Toru ; Misao, Yu ; Esposito, Grazia ; Gonzalez, Arantxa ; Vitale, Serena ; Parolin, Carola ; Yasuzawa-Amano, Saori ; Muraski, John ; De Angelis, Antonella ; LeCapitaine, Nicole ; Siggins, Robert W. ; Loredo, Maria ; Bearzi, Claudia ; Bolli, Roberto ; Urbanek, Konrad ; Leri, Annarosa ; Kajstura, Jan ; Anversa, Piero. / Formation of large coronary arteries by cardiac progenitor cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 5. pp. 1668-1673.
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AU - Tillmanns, Jochen

AU - Rota, Marcello

AU - Hosoda, Toru

AU - Misao, Yu

AU - Esposito, Grazia

AU - Gonzalez, Arantxa

AU - Vitale, Serena

AU - Parolin, Carola

AU - Yasuzawa-Amano, Saori

AU - Muraski, John

AU - De Angelis, Antonella

AU - LeCapitaine, Nicole

AU - Siggins, Robert W.

AU - Loredo, Maria

AU - Bearzi, Claudia

AU - Bolli, Roberto

AU - Urbanek, Konrad

AU - Leri, Annarosa

AU - Kajstura, Jan

AU - Anversa, Piero

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N2 - Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1α, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.

AB - Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1α, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.

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