Bone marrow cells adopt the cardiomyogenic fate in vivo

Marcello Rota, Jan Kajstura, Toru Hosoda, Claudia Bearzi, Serena Vitale, Grazia Esposito, Grazia Iaffaldano, M. Elena Padin-Iruegas, Arantxa Gonzalez, Roberto Rizzi, Narissa Small, John Muraski, Roberto Alvarez, Xiongwen Chen, Konrad Urbanek, Roberto Bolli, Steven R. Houser, Annarosa Leri, Mark A. Sussman, Piero Anversa

Research output: Contribution to journalArticle

Abstract

The possibility that adult bone marrow cells (BMCs) retain a remarkable degree of developmental plasticity and acquire the cardiomyocyte lineage after infarction has been challenged, and the notion of BMC transdifferentiation has been questioned. The center of the controversy is the lack of unequivocal evidence in favor of myocardial regeneration by the injection of BMCs in the infarcted heart. Because of the interest in cell-based therapy for heart failure, several approaches including gene reporter assay, genetic tagging, cell genotyping, PCR-based detection of donor genes, and direct immunofluorescence with quantum dots were used to prove or disprove BMC transdifferentiation. Our results indicate that BMCs engraft, survive, and grow within the spared myocardium after infarction by forming junctional complexes with resident myocytes. BMCs and myocytes express at their interface connexin 43 and N-cadherin, and this interaction may be critical for BMCs to adopt the cardiomyogenic fate. With time, a large number of myocytes and coronary vessels are generated. Myocytes show a diploid DNA content and carry, at most, two sex chromosomes. Old and new myocytes show synchronicity in calcium transients, providing strong evidence in favor of the functional coupling of these two cell populations. Thus, BMCs transdifferentiate and acquire the cardiomyogenic and vascular phenotypes restoring the infarcted heart. Together, our studies reveal that locally delivered BMCs generate de novo myocardium composed of integrated cardiomyocytes and coronary vessels. This process occurs independently of cell fusion and ameliorates structurally and functionally the outcome of the heart after infarction.

Original languageEnglish (US)
Pages (from-to)17783-17788
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number45
DOIs
StatePublished - Nov 6 2007
Externally publishedYes

Fingerprint

Bone Marrow Cells
Muscle Cells
Cell Transdifferentiation
Infarction
Cardiac Myocytes
Coronary Vessels
Myocardium
Quantum Dots
Direct Fluorescent Antibody Technique
Connexin 43
Sex Chromosomes
Cell Fusion
Cadherins
Cell- and Tissue-Based Therapy
Diploidy
Reporter Genes
Blood Vessels
Regeneration
Heart Failure
Calcium

Keywords

  • Myocardial infarction
  • Myocardial regeneration
  • Stem cells
  • Transdifferentiation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Rota, M., Kajstura, J., Hosoda, T., Bearzi, C., Vitale, S., Esposito, G., ... Anversa, P. (2007). Bone marrow cells adopt the cardiomyogenic fate in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104(45), 17783-17788. https://doi.org/10.1073/pnas.0706406104

Bone marrow cells adopt the cardiomyogenic fate in vivo. / Rota, Marcello; Kajstura, Jan; Hosoda, Toru; Bearzi, Claudia; Vitale, Serena; Esposito, Grazia; Iaffaldano, Grazia; Padin-Iruegas, M. Elena; Gonzalez, Arantxa; Rizzi, Roberto; Small, Narissa; Muraski, John; Alvarez, Roberto; Chen, Xiongwen; Urbanek, Konrad; Bolli, Roberto; Houser, Steven R.; Leri, Annarosa; Sussman, Mark A.; Anversa, Piero.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 45, 06.11.2007, p. 17783-17788.

Research output: Contribution to journalArticle

Rota, M, Kajstura, J, Hosoda, T, Bearzi, C, Vitale, S, Esposito, G, Iaffaldano, G, Padin-Iruegas, ME, Gonzalez, A, Rizzi, R, Small, N, Muraski, J, Alvarez, R, Chen, X, Urbanek, K, Bolli, R, Houser, SR, Leri, A, Sussman, MA & Anversa, P 2007, 'Bone marrow cells adopt the cardiomyogenic fate in vivo', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 45, pp. 17783-17788. https://doi.org/10.1073/pnas.0706406104
Rota, Marcello ; Kajstura, Jan ; Hosoda, Toru ; Bearzi, Claudia ; Vitale, Serena ; Esposito, Grazia ; Iaffaldano, Grazia ; Padin-Iruegas, M. Elena ; Gonzalez, Arantxa ; Rizzi, Roberto ; Small, Narissa ; Muraski, John ; Alvarez, Roberto ; Chen, Xiongwen ; Urbanek, Konrad ; Bolli, Roberto ; Houser, Steven R. ; Leri, Annarosa ; Sussman, Mark A. ; Anversa, Piero. / Bone marrow cells adopt the cardiomyogenic fate in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 45. pp. 17783-17788.
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AU - Rota, Marcello

AU - Kajstura, Jan

AU - Hosoda, Toru

AU - Bearzi, Claudia

AU - Vitale, Serena

AU - Esposito, Grazia

AU - Iaffaldano, Grazia

AU - Padin-Iruegas, M. Elena

AU - Gonzalez, Arantxa

AU - Rizzi, Roberto

AU - Small, Narissa

AU - Muraski, John

AU - Alvarez, Roberto

AU - Chen, Xiongwen

AU - Urbanek, Konrad

AU - Bolli, Roberto

AU - Houser, Steven R.

AU - Leri, Annarosa

AU - Sussman, Mark A.

AU - Anversa, Piero

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N2 - The possibility that adult bone marrow cells (BMCs) retain a remarkable degree of developmental plasticity and acquire the cardiomyocyte lineage after infarction has been challenged, and the notion of BMC transdifferentiation has been questioned. The center of the controversy is the lack of unequivocal evidence in favor of myocardial regeneration by the injection of BMCs in the infarcted heart. Because of the interest in cell-based therapy for heart failure, several approaches including gene reporter assay, genetic tagging, cell genotyping, PCR-based detection of donor genes, and direct immunofluorescence with quantum dots were used to prove or disprove BMC transdifferentiation. Our results indicate that BMCs engraft, survive, and grow within the spared myocardium after infarction by forming junctional complexes with resident myocytes. BMCs and myocytes express at their interface connexin 43 and N-cadherin, and this interaction may be critical for BMCs to adopt the cardiomyogenic fate. With time, a large number of myocytes and coronary vessels are generated. Myocytes show a diploid DNA content and carry, at most, two sex chromosomes. Old and new myocytes show synchronicity in calcium transients, providing strong evidence in favor of the functional coupling of these two cell populations. Thus, BMCs transdifferentiate and acquire the cardiomyogenic and vascular phenotypes restoring the infarcted heart. Together, our studies reveal that locally delivered BMCs generate de novo myocardium composed of integrated cardiomyocytes and coronary vessels. This process occurs independently of cell fusion and ameliorates structurally and functionally the outcome of the heart after infarction.

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