p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo.
p53 is an important modulator of stem cell fate, but its role in cardiac progenitor cells (CPCs) is unknown. Here, we tested the effects of a single extra-copy of p53 on the function of CPCs in the presence of oxidative stress mediated by doxorubicin in vitro and type-1 diabetes in vivo. CPCs were obtained from super-p53 transgenic mice (p53-tg), in which the additional allele is regulated in a manner similar to the endogenous protein. Old CPCs with increased p53 dosage showed a superior ability to sustain oxidative stress, repair DNA damage and restore cell division. With doxorubicin, a larger fraction of CPCs carrying an extra-copy of the p53 allele recruited γH2A.X reestablishing DNA integrity. Enhanced p53 expression resulted in a superior tolerance to oxidative stress in vivo by providing CPCs with defense mechanisms necessary to survive in the milieu of the diabetic heart; they engrafted in regions of tissue injury and in three days acquired the cardiomyocyte phenotype. The biological advantage provided by the increased dosage of p53 in CPCs suggests that this genetic strategy may be translated to humans to increase cellular engraftment and growth, critical determinants of successful cell therapy for the failing heart.
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ramaswamy
R
Kannappan
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland.
Alex
A
Matsuda
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
João
J
Ferreira-Martins
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Eric
E
Zhang
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Giorgia
G
Palano
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland.
Anna
A
Czarna
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Mauricio Castro
MC
Cabral-Da-Silva
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Adriana
A
Bastos-Carvalho
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Fumihiro
F
Sanada
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Noriko
N
Ide
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Marcello
M
Rota
Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain.
Maria A
MA
Blasco
Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain.
Manuel
M
Serrano
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland.
Piero
P
Anversa
Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland. Electronic address: annarosa.leri@cardiocentro.org.
Annarosa
A
Leri
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D006657:Histones; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse
DNA repair; Diabetes; Stem cell engraftment; Stem cell fate