Hyaluronan mixed esters of butyric and retinoic Acid drive cardiac and endothelial fate in term placenta human mesenchymal stem cells and enhance cardiac repair in infarcted rat hearts.
We have developed a mixed ester of hyaluronan with butyric and retinoic acid (HBR) that acted as a novel cardiogenic/vasculogenic agent in human mesenchymal stem cells isolated from bone marrow, dental pulp, and fetal membranes of term placenta (FMhMSCs). HBR remarkably enhanced vascular endothelial growth factor (VEGF), KDR, and hepatocyte growth factor (HGF) gene expression and the secretion of the angiogenic, mitogenic, and antiapoptotic factors VEGF and HGF, priming stem cell differentiation into endothelial cells. HBR also increased the transcription of the cardiac lineage-promoting genes GATA-4 and Nkx-2.5 and the yield of cardiac markerexpressing cells. These responses were notably more pronounced in FMhMSCs. FMhMSC transplantation into infarcted rat hearts was associated with increased capillary density, normalization of left ventricular function, and significant decrease in scar tissue. Transplantation of HBR-preconditioned FMhM-SCs further enhanced capillary density and the yield of human vWF-expressing cells, additionally decreasing the infarct size. Some engrafted, HBR-pretreated FMhMSCs were also positive for connexin 43 and cardiac troponin I. Thus, the beneficial effects of HBR-exposed FMhMSCs may be mediated by a large supply of angiogenic and antiapoptotic factors, and FMhMSC differentiation into vascular cells. These findings may contribute to further development in cell therapy of heart failure.
Ventura
Carlo
C
Laboratory of Molecular Biology and Stem Cell Engineering, Institute of Cardiology, National Institute of Biostructures and Biosystems, University of Bologna, Bologna, Italy. carlo.ventura@unibo.it
Cantoni
Silvia
S
Bianchi
Francesca
F
Lionetti
Vincenzo
V
Cavallini
Claudia
C
Scarlata
Ignazio
I
Foroni
Laura
L
Maioli
Margherita
M
Bonsi
Laura
L
Alviano
Francesco
F
Fossati
Valentina
V
Bagnara
Gian Paolo
GP
Pasquinelli
Gianandrea
G
Recchia
Fabio A
FA
Perbellini
Alberto
A
D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D004952:Esters / Q000494:pharmacology; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000187:drug effects*; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D009203:Myocardial Infarction / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D010920:Placenta / Q000166:cytology*; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left
D004952:Esters; D050991:GATA4 Transcription Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020148:Butyric Acid; D014212:Tretinoin; D006820:Hyaluronic Acid