Oxidative Stress as a Critical Determinant of Adult Cardiac Progenitor Cell-Fate Decisions

2019 ◽  
pp. 339-363
Author(s):  
Diego Herrero ◽  
Susana Cañón ◽  
Guillermo Albericio ◽  
Susana Aguilar ◽  
Rosa María Carmona ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Critical Determinant ◽  
Cardiac Progenitor Cell ◽  
Cell Fate Decisions

scholarly journals Single cell RNA-seq and ATAC-seq indicate critical roles of Isl1 and Nkx2-5 for cardiac progenitor cell transition states and lineage settlement

2017 ◽  
Author(s):  
Guangshuai Jia ◽  
Jens Preussner ◽  
Stefan Guenther ◽  
Xuejun Yuan ◽  
Michail Yekelchyk ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Regulatory Networks ◽  
Progenitor Cell ◽  
Marker Gene ◽  
Transitional Cell ◽  
Developmental Trajectory ◽  
Open Chromatin ◽  
Cardiac Progenitor Cell ◽  
Cell Fate Decisions

SUMMARYFormation and segregation of cell lineages building the vertebrate heart have been studied extensively by genetic cell tracing techniques and by analysis of single marker gene expression but the underlying gene regulatory networks driving cell fate transitions during early cardiogenesis are only partially understood. Here, we comprehensively characterized mouse cardiac progenitor cells (CPC) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing. By leveraging on cell-to-cell heterogeneity, we identified different previously unknown cardiac sub-populations. Reconstruction of the developmental trajectory revealed that Isl1+ CPC represent a transitional cell population maintaining a prolonged multipotent state, whereas extended expression of Nkx2-5 commits CPC to a unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states, which critically depend on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution.

scholarly journals Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions

Cell Reports ◽  
2021 ◽  
Vol 34 (10) ◽  
pp. 108818
Author(s):  
Luca Orlando ◽  
Borko Tanasijevic ◽  
Mio Nakanishi ◽  
Jennifer C. Reid ◽  
Juan L. García-Rodríguez ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Histone Variant ◽  
Phosphorylation State ◽  
Cell Fate Decisions

Abstract 340: Short Telomeres Induce Autophagy and Modulate Cardiac Progenitor Cell Fate

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Nirmala Hariharan ◽  
Collin Matsumoto ◽  
Jacqueline Emathinger ◽  
Saba Daneshpooy ◽  
Minyoung Shin ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Smooth Muscle Actin ◽  
Wild Mouse ◽  
Degradation Process ◽  
Mouse Strains ◽  
Therapeutic Effects ◽  
Cardiac Progenitor Cell ◽  
Altered Cell ◽  
The Impact

Aging severely limits myocardial 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 hypothesize that short telomeres induce autophagy and elicit the age-associated change in cardiac progenitor cell fate. We compared mouse strains with different telomere lengths (TL) for phenotypic characteristics of aging and also isolated CPCs from them. Naturally occurring wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres (TL:18Kb) exhibits early cardiac aging with diastolic dysfunction, hypertrophy, fibrosis and increase in senescence markers p53 and p16, as compared to common lab strains FVB (TL:75Kb) and C57 (TL:50Kb). CAST CPCs with short TLs have altered cell fate as characterized by slower proliferation (p<0.01); increased senescence identified by beta-galactosidase activity (p<0.05); increased basal commitment as determined by expression of lineage markers smooth muscle actin, Tie2, and sarcomeric actinin (16.6, 1.7 and 1.75, p<0.05); as well as loss of quiescence marker expression. Consistent findings of altered cell fate are also evident in old CPCs isolated from aged mice with significantly shorter TLs. Cell fate changes occurring downstream from short TL are at least partially p53 dependent, as p53 inhibition rescues the irreversible cell cycle arrest observed in CAST CPCs. Mechanistically, short TLs induce autophagy, a catabolic protein degradation process. Autophagy flux is increased in CAST CPCs as evidenced by increased LC3 (p<0.05), reduced p62 expression (-52%, p<0.05) and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation, but not autolysosome formation reverses the cell fate to a more youthful phenotype. Overall the data suggests that short TLs activate autophagy to accommodate cell fate changes that tip the equilibrium away from quiescence and proliferation into differentiation and senescence, leading to age-associated exhaustion of CPCs. The study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to enhance the therapeutic effects of aged CPCs.

Abstract 356: Krueppel-Like Factor 15 Regulates Wnt/β-Catenin Transcription and Controls Cardiac Progenitor Cell Fate in the Postnatal Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Claudia Noack ◽  
Maria P Zafiriou ◽  
Anke Renger ◽  
Hans J Schaeffer ◽  
Martin W Bergmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Activation ◽  
Progenitor Cell ◽  
Cellular Localization ◽  
Target Genes ◽  
Critical Role ◽  
Isolated Cells ◽  
Cardiac Progenitor Cell

Wnt/β-catenin signaling controls adult heart remodeling partly by regulating cardiac progenitor cell (CPC) differentiation. We now identified and characterized a novel cardiac interaction of the transcription factor Krueppel-like factor 15 (KLF15) with the Wnt/β-catenin signaling on adult CPCs. In vitro mutation, reporter gene assays and co-localization studies revealed that KLF15 requires two distinct domains for nuclear localization and for repression of β-catenin-mediated transcription. KLF15 had no effect on β-catenin stability or cellular localization, but interacted with its co-factor TCF4, which is required for activation of β-catenin target gene expression. Moreover, increased TCF4 ubiquitination was induced by KLF15. In line with this finding we found KLF15 to interact with the Nemo-like kinase, which was shown to phosphorylate and target TCF4 for degradation. In vivo analyses of adult Klf15 functional knock-out (KO) vs. wild-type (WT) mice showed a cardiac β-catenin-mediated transcriptional activation and reduced TCF4 degradation along with cardiac dysfunction assessed by echocardiography (n=10). FACS analysis of the CPC enriched-population of KO vs. WT mice revealed a significant reduction of cardiogenic-committed precursors identified as Sca1+/αMHC+ (0.8±0.2% vs. 1.8±0.1%) and Tbx5+ (3.5±0.3% vs. 5.2±0.5%). In contrast, endothelial Sca1+/CD31+ cells were significantly higher in KO mice (11.3±0.4% vs. 8.6±0.4%; n≥9). In addition, Sca1+ isolated cells of Klf15 KO showed increased RNA expression of endothelial markers von Willebrand Factor, CD105, and Flk1 along with upregulation of β-catenin target genes. CPCs co-cultured on adult fibroblasts resulted in increased endothelial Flk1 cells and reduction of αMHC and Hand1 cardiogenic cells in KO vs. WT CPCs (n=9). Treating these co-cultures with Quercetin, an inhibitor of nuclear β-catenin, resulted in partial rescue of the observed phenotype. This study uncovers a critical role of KLF15 for the maintenance of cardiac tissue homeostasis. Via inhibition of β-catenin transcription, KLF15 controls cardiomyogenic cell fate similar to embryonic cardiogenesis. This knowledge may provide a tool for activation of endogenous CPCs in the postnatal heart.

Extrinsic and intrinsic factors control the genesis of amacrine and cone cells in the rat retina

Development ◽  
1999 ◽  
Vol 126 (3) ◽  
pp. 555-566 ◽  
Author(s):  
M.J. Belliveau ◽  
C.L. Cepko
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Amacrine Cell ◽  
Amacrine Cells ◽  
Environment Change ◽  
Rat Retina ◽  
Cell Fate Decisions ◽  
Cone Cells ◽  
Postnatal Environment

The seven major classes of cells of the vertebrate neural retina are generated from a pool of multipotent progenitor cells. Recent studies suggest a model of retinal development in which both the progenitor cells and the environment change over time (Cepko, C. L., Austin, C. P., Yang, X., Alexiades, M. and Ezzeddine, D. (1996). Proc. Natl. Acad. Sci. USA 93, 589–595). We have utilized a reaggregate culture system to test this model. A labeled population of progenitors from the embryonic rat retina were cultured with an excess of postnatal retinal cells and then assayed for their cell fate choices. We found that the postnatal environment had at least two signals that affected the embryonic cells' choice of fate; one signal inhibited the production of amacrine cells and a second affected the production of cone cells. No increase in cell types generated postnatally was observed. The source of the inhibitor of the amacrine cell fate appeared to be previously generated amacrine cells, suggesting that amacrine cell number is controlled by feedback inhibition. The progenitor cell lost its ability to be inhibited for production of an amacrine cell as it entered M phase of the cell cycle. We suggest that postmitotic cells influence progenitor cell fate decisions, but that they do so in a manner restricted by the intrinsic biases of progenitor cells.

scholarly journals Hyaluronan-Based Three-Dimensional Microenvironment Potently Induces Cardiovascular Progenitor Cell Populations

2013 ◽  
Vol 2013 ◽  
pp. 1-7
Author(s):  
Jessica M. Gluck ◽  
Jennifer Chyu ◽  
Connor Delman ◽  
Sepideh Heydarkhan-Hagvall ◽  
W. Robb MacLellan ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Three Dimensional ◽  
Extrinsic Factors ◽  
Cell Fate Decisions ◽  
3D Microenvironment ◽  
Cell Niche ◽  
The Relationship ◽  
Stem Cell Niches

The relationship between stem cell niches in vivo and their surrounding microenvironment is still relatively unknown. Recent advances have indicated that extrinsic factors within the cardiovascular progenitor cell niche influence maintenance of a multipotent state as well as drive cell-fate decisions. We have previously shown the direct effects of extracellular matrix (ECM) proteins and have now investigated the effects of dimension on the induction of a cardiovascular progenitor cell (CPC) population. We have shown here that the three-dimensionality of a hyaluronan-based hydrogel greatly induces a CPC population, as marked by Flk-1. We have compared the effects of a 3D microenvironment to those of conventional 2D cell culture practices and have found that the 3D microenvironment potently induces a progenitor cell state.

scholarly journals TrkB/BDNF signaling regulates photoreceptor progenitor cell fate decisions

2006 ◽  
Vol 299 (2) ◽  
pp. 455-465 ◽  
Author(s):  
Brian A. Turner ◽  
Janet Sparrow ◽  
Bolin Cai ◽  
Julie Monroe ◽  
Takashi Mikawa ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Cell Fate Decisions ◽  
Bdnf Signaling

scholarly journals Reconstruction of rat retinal progenitor cell lineages in vitro reveals a surprising degree of stochasticity in cell fate decisions

Development ◽  
2010 ◽  
Vol 138 (2) ◽  
pp. 227-235 ◽  
Author(s):  
F. L. A. F. Gomes ◽  
G. Zhang ◽  
F. Carbonell ◽  
J. A. Correa ◽  
W. A. Harris ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Retinal Progenitor Cell ◽  
Cell Fate Decisions ◽  
Cell Lineages ◽  
Retinal Progenitor

scholarly journals The Spatiotemporal Expression of Notch1 and Numb and Their Functional Interaction during Cardiac Morphogenesis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2192
Author(s):  
Lianjie Miao ◽  
Yangyang Lu ◽  
Anika Nusrat ◽  
Hala Y. Abdelnasser ◽  
Sayantap Datta ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Structural Defects ◽  
Asymmetric Distribution ◽  
Cardiomyocyte Proliferation ◽  
Double Knockout ◽  
Cardiac Morphogenesis ◽  
Cardiac Progenitor Cell ◽  
Notch Activation

Numb family proteins (NFPs), including Numb and Numblike (Numbl), are commonly known for their role as cell fate determinants for multiple types of progenitor cells, mainly due to their function as Notch inhibitors. Previous studies have shown that myocardial NFP double knockout (MDKO) hearts display an up-regulated Notch activation and various defects in cardiac progenitor cell differentiation and cardiac morphogenesis. Whether enhanced Notch activation causes these defects in MDKO is not fully clear. To answer the question, we examined the spatiotemporal patterns of Notch1 expression, Notch activation, and Numb expression in the murine embryonic hearts using multiple approaches including RNAScope, and Numb and Notch reporter mouse lines. To further interrogate the interaction between NFPs and Notch signaling activation, we deleted both Notch1 or RBPJk alleles in the MDKO. We examined and compared the phenotypes of Notch1 knockout, NFPs double knockout, Notch1; Numb; Numbl and RBPJk; Numb; Numbl triple knockouts. Our study showed that Notch1 is expressed and activated in the myocardium at several stages, and Numb is enriched in the epicardium and did not show the asymmetric distribution in the myocardium. Cardiac-specific Notch1 deletion causes multiple structural defects and embryonic lethality. Notch1 or RBPJk deletion in MDKO did not rescue the structural defects in the MDKO but partially rescued the defects of cardiac progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis. Our study concludes that NFPs regulate progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis partially through Notch1 and play more roles than inhibiting Notch1 signaling during cardiac morphogenesis.

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