p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo

Abstract

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.

Gata4-Dependent Differentiation of c-Kit + –Derived Endothelial Cells Underlies Artefactual Cardiomyocyte Regeneration in the Heart

“…However, the potential to genetically reprogram c-Kit–derived cells and other cardiac mesenchymal cells into cardiomyocytes remains attractive for future development. 25 , 26 …”

Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate

“…Establishing the signaling mechanism underlying autophagy regulation in CAST CPCs prompted examination of the role of p53, based on prior evidence demonstrating that p53 regulates senescence[11] and cell fate of CPCs[23] and induces autophagy in cardiac cells[42]. Stable knockdown of p53 (−28%, Fig.…”

“…Interestingly, a recent study by Kannappan et al demonstrates that CPCs isolated from transgenic mice with a single extra copy of p53 (super-p53 mice) display a younger phenotype with higher proliferation, lower senescence marker expression and increased DNA damage repair[23]. Unlike transgenic mice with constitutively active p53, the super-p53 mice exhibit moderately higher p53 activity and regulation by post-translational modifications that is similar to the endogenous gene[23]. Reconciling our findings with Kanappan et al, it appears that the dose of p53 and method of regulation is critical for modulation of CPC youth.…”

“…Transcription factor p53 functions as a cell-cycle inhibitor and is activated in response to telomere and DNA damage, aging and pathologic stress in the heart[2, 20–22]. p53 modulates stem cell fate by exerting pleiotropic roles that impact cell survival, differentiation, senescence and quiescence[23, 24]. Additionally, p53 regulates autophagy, a catabolic process of bulk protein degradation, in a cell-type specific manner[25].…”

Engineered Aging Cardiac Tissue Chip Model for Studying Cardiovascular Disease

“…In vitro, morphologically senescent cells are large, flat, vacuolized, and, sometimes, multinucleated [Muñoz-Espín and Serrano, 2014]. The distinct molecular features of senescent cells are chronic DNA damage response (DDR), accumulated DDR foci, increased expression of cell cycle inhibitors like p26, p21, and p53, growth factors like TGFΒ, expression of the senescence-associated marker p16 INK4a , accumulation of reactive oxygen species (ROS) [Kortlever et al, 2006[Kortlever et al, , 2008Elzi et al, 2012;Malaquin et al, 2015;Kannappan et al, 2017Kannappan et al, , 2019.…”