Placental stem cells pre-treated with a hyaluronan mixed ester of butyric and retinoic acid to cure infarcted pig hearts: a multimodal study.
OBJECTIVE
Pre-treating placenta-derived human mesenchymal stem cells (FMhMSCs) with a hyaluronan mixed ester of butyric and retinoic acid (HBR) potentiates their reparative capacity in rodent hearts. Our aim was to test FMhMSCs in a large-animal model by employing a novel combination of in vivo and ex vivo analyses.


RESULTS
Matched regional quantifications of myocardial function and viability were performed by magnetic resonance imaging (MRI) and positron emission tomography (PET) 4 weeks after myocardial infarction combined with intramyocardial injection of FMhMSCs (n = 7), or HBR-pre-treated FMhMSCs (HBR-FMhMSCs, n = 6), or saline solution (PBS, n = 7). Sham-operated pigs (n = 4) were used as control animals. Despite no differences in the ejection fraction and haemodynamics, regional MRI revealed, in pigs treated with HBR-FMhMSCs compared with the other infarcted groups, a 40% smaller infarct scar size and a significant improvement of the end-systolic wall thickening and circumferential shortening of the infarct border zone. Consistently, PET showed that myocardial perfusion and glucose uptake were, respectively, 35 and 23% higher in the border zone of pigs treated with HBR-FMhMSCs compared with the other infarcted groups. Histology supported in vivo imaging; the delivery of HBR-FMhMSCs significantly enhanced capillary density and decreased fibrous tissue by approximately 68%. Moreover, proteomic analysis of the border zone in the HBR-FMhMSCs group and the FMhMSCs group indicated, respectively, 45 and 30% phenotypic homology with healthy tissue, while this homology was only 26% in the border zone of the PBS group.


CONCLUSIONS
Our results support a more pronounced reparative potential of HBR-pre-treated FMhMSCs in a clinically relevant animal model of infarction and highlight the necessity of using combined diagnostic imaging to avoid underestimations of stem cell therapeutic effects in the heart.
Guppo Intini-SMA Laboratory of Experimental Cardiology, Scuola Superiore Sant'Anna, I-56124 Pisa, Italy.
Anca
A
Simioniuc
Manuela
M
Campan
Vincenzo
V
Lionetti
Martina
M
Marinelli
Giovanni D
GD
Aquaro
Claudia
C
Cavallini
Sabrina
S
Valente
Dario
D
Di Silvestre
Silvia
S
Cantoni
Fabio
F
Bernini
Claudia
C
Simi
Silvia
S
Pardini
Pierluigi
P
Mauri
Danilo
D
Neglia
Carlo
C
Ventura
Gianandrea
G
Pasquinelli
Fabio A
FA
Recchia
D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology; D004952:Esters / Q000494:pharmacology; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D010920:Placenta / Q000166:cytology; D049268:Positron-Emission Tomography; D011247:Pregnancy; D040901:Proteomics; D034421:Sus scrofa; D014212:Tretinoin / Q000494:pharmacology; D016277:Ventricular Function, Left
D004952:Esters; D020148:Butyric Acid; D014212:Tretinoin; D006820:Hyaluronic Acid