Short Telomeres Induce p53 and Autophagy and Modulate Age‐Associated Changes in Cardiac Progenitor Cell Fate. (25th February 2018)

• Record Type: Journal Article
• Authors: Matsumoto, Collin; Jiang, Yan; Emathinger, Jacqueline; Quijada, Pearl; Nguyen, Nathalie; De La Torre, Andrea; Moshref, Maryam; Nguyen, Jonathan; Levinson, Aimee B.; Shin, Minyoung; Sussman, Mark A.; Hariharan, Nirmala
• Is Part Of: Stem cells. Volume 36:Number 6(2018)
• Page Start: 868
• Page End: 880
• Publication Date: 2018-02-25
• Subjects: Cardiac progenitor cells -- Aging -- Telomeres -- p53 -- Autophagy; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2793
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract: Aging severely limits myocardial repair and regeneration. Delineating the impact of age‐associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age‐associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age‐associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868–880 Abstract : Schematic of hypothetical signaling cascade. The cell fate of CPCs changes with age and is characterized by a switch away from proliferation and quiescence (reversible form of cell cycle arrest) toward senescence and increased basal commitment (irreversible forms of cell cycle arrest) accounting for age‐associated stem cell exhaustion.Mechanistically, short telomeres activate p53 that induces autophagy and at least partially contributes to the age‐associated change in cell fate. Blunting telomere shortening via overexpression of TERT‐WT, silencing p53, or treating with pharmacological inhibitors of p53 (PFT) and autophagy (3‐MA, Ulk1‐In, BF) selectively attenuate senescence and basal commitment and reverse cell fate of aged CPCs. Abbreviations: BF, bafilomycin; CPC, cardiac progenitor cells; TERT‐WT, wild‐type telomerase reverse transcriptase; Sh‐p53, Short hairpin RNA against p53; PFT, Pifithrin‐a 3‐MA, 3‐Methyl Adenine; Ulk1‐In, Ulk1 inhibitor.