Hyaluronan mixed esters of butyric and retinoic acid affording myocardial survival and repair without stem cell transplantation.
Possible cardiac repair by adult stem cell transplantation is currently hampered by poor cell viability and delivery efficiency, uncertain differentiating fate in vivo, the needs of ex vivo cell expansion, and consequent delay in transplantation after the onset of heart attack. By the aid of magnetic resonance imaging, positron emission tomography, and immunohistochemistry, we show that injection of a hyaluronan mixed ester of butyric and retinoic acid (HBR) into infarcted rat hearts afforded substantial cardiovascular repair and recovery of myocardial performance. HBR restored cardiac [(18)F]fluorodeoxyglucose uptake and increased capillary density and led to the recruitment of endogenous Stro-1-positive stem cells. A terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay demonstrated that HBR-treated hearts exhibited a decrease in the number of apoptotic cardiomyocytes. In isolated rat cardiomyocytes and Stro-1 stem cells, HBR enhanced the transcription of vascular endothelial growth factor, hepatocyte growth factor, kdr, akt, and pim-1. HBR also increased the secretion of vascular endothelial growth factor and hepatocyte growth factor, suggesting that the mixed ester may have recruited both myocardial and Stro-1 cells also. An increase in capillarogenesis was induced in vitro with medium obtained from HBR-exposed cells. In the infarcted myocardium, HBR injection increased histone H4 acetylation significantly. Acetyl-H4 immunoreactivity increased in rat cardiomyocytes and Stro-1 cells exposed to HBR, compared with untreated cells. In conclusion, efficient cardiac regenerative therapy can be afforded by HBR without the need of stem cell transplantation or vector-mediated gene delivery.
Lionetti
Vincenzo
V
Sector of Medicine, Scuola Superiore S. Anna, I-56124 Pisa, Italy; Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche Fondazione G. Monasterio, I-56124 Pisa, Italy.
Cantoni
Silvia
S
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Cavallini
Claudia
C
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Bianchi
Francesca
F
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Valente
Sabrina
S
Department of Hematology, Oncology, and Clinical Pathology, University of Bologna, I-40138 Bologna, Italy.
Frascari
Irene
I
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Olivi
Elena
E
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Aquaro
Giovanni D
GD
Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche Fondazione G. Monasterio, I-56124 Pisa, Italy.
Bonavita
Francesca
F
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Scarlata
Ignazio
I
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Maioli
Margherita
M
Department of Biomedical Sciences, University of Sassari, I-07100 Sassari, Italy.
Vaccari
Valentina
V
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Tassinari
Riccardo
R
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino.
Bartoli
Antonietta
A
Department of Physics, University of Pisa, I-56124 Pisa, Italy.
Recchia
Fabio A
FA
Sector of Medicine, Scuola Superiore S. Anna, I-56124 Pisa, Italy; Department of Physiology, New York Medical College, Valhalla, New York 10595.
Pasquinelli
Gianandrea
G
Department of Hematology, Oncology, and Clinical Pathology, University of Bologna, I-40138 Bologna, Italy.
Ventura
Carlo
C
Laboratory of Molecular Biology and Stem Cell Engineering, Cardiovascular Department-National Institute of Biostructures and Biosystems, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy; Bioscience Institute, RSM-47891 Falciano, Republic of San Marino. Electronic address: carlo.ventura@unibo.it.
D000818:Animals; D020148:Butyric Acid / Q000737:chemistry*; D002470:Cell Survival; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D018014:Gene Transfer Techniques; D006820:Hyaluronic Acid / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009389:Neovascularization, Pathologic; D049268:Positron-Emission Tomography / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D033581:Stem Cell Transplantation / Q000379:methods*; D014212:Tretinoin / Q000737:chemistry* / Q000378:metabolism
D019788:Fluorodeoxyglucose F18; D020148:Butyric Acid; D014212:Tretinoin; D006820:Hyaluronic Acid