Abstract 011: Transcriptional Basis Of Epicardial Progenitor Cell Activation During Heart Development, Regeneration And Repair

The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in reactivation of epicardial progenitor cells, which reengages a developmental gene program, but the underlying transcriptional basis has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on C/EBP, HOX, MEIS, and GRAINYHEAD families of transcription factors. Furthermore, disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial progenitor cell activation during heart development and injury, providing a platform for enhancing cardioprotection and regeneration.

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Dissecting the Complexity of Early Heart Progenitor Cells

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd9010005 ◽

2021 ◽

Vol 9 (1) ◽

pp. 5

Author(s):

Miquel Sendra ◽

Jorge Domínguez ◽

Miguel Torres ◽

Oscar Ocaña

Keyword(s):

Progenitor Cells ◽

Heart Development ◽

Functional Role ◽

Cardiac Development ◽

Heart Defects ◽

Heart Tube ◽

Cell Sources ◽

Key Aspects ◽

Functional Analyses ◽

Lineage Diversification

Early heart development depends on the coordinated participation of heterogeneous cellsources. As pioneer work from Adriana C. Gittenberger-de Groot demonstrated, characterizing thesedistinct cell sources helps us to understand congenital heart defects. Despite decades of researchon the segregation of lineages that form the primitive heart tube, we are far from understanding itsfull complexity. Currently, single-cell approaches are providing an unprecedented level of detail oncellular heterogeneity, offering new opportunities to decipher its functional role. In this review, wewill focus on three key aspects of early heart morphogenesis: First, the segregation of myocardial andendocardial lineages, which yields an early lineage diversification in cardiac development; second,the signaling cues driving differentiation in these progenitor cells; and third, the transcriptionalheterogeneity of cardiomyocyte progenitors of the primitive heart tube. Finally, we discuss howsingle-cell transcriptomics and epigenomics, together with live imaging and functional analyses, willlikely transform the way we delve into the complexity of cardiac development and its links withcongenital defects.

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Chromatin alterations in the aging lung change progenitor cell activity

10.1101/2021.07.15.452072 ◽

2021 ◽

Author(s):

Samuel P. Rowbotham ◽

Patrizia Pessina ◽

Carolina Garcia de Alba Rivas ◽

Jingyun Li ◽

Irene Wong ◽

...

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

Cell Activity ◽

Cell Types ◽

Chromatin Accessibility ◽

Alveolar Type ◽

Aged Mouse ◽

Efficient Manner ◽

Age Related ◽

Multipotent Progenitor Cells

The lung contains multiple progenitor cell types that respond to damage, but how their responses are choreographed and why they decline with age is poorly understood. We report that histone H3 lysine 9 di-methylation (K9me2), mediated by histone methyltransferase G9a, regulates the dynamics of lung epithelial progenitor cells, and this regulation deteriorates with age. In aged mouse lungs, K9me2 loss coincided with lower frequency and activity of alveolar type 2 (AT2) cell progenitors. In contrast, K9me2 loss resulted in increased frequency and activity of multipotent progenitor cells with bronchiolar and alveolar potential (BASCs) and bronchiolar progenitors. K9me2 depletion in young mice through deletion or inhibition of G9a decreased AT2 progenitor activity and impaired alveolar injury regeneration. Conversely, K9me2 depletion increased chromatin accessibility of bronchiolar cell genes, increased BASC frequency and accelerated bronchiolar repair. K9me2 depletion also resulted in increased bronchiolar cell expression of the SARS-CoV2 receptor Ace2 in aged lungs. These data point to K9me2 and G9a as a critical regulator of the balance of lung progenitor cell regenerative responses and prevention of susceptibility to age-related lung diseases. These findings indicate that epigenetic regulation coordinates progenitor cell populations to expedite regeneration in the most efficient manner and disruption of this regulation presents significant challenges to lung health.

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The Adult Pituitary Shows Stem/Progenitor Cell Activation in Response to Injury and Is Capable of Regeneration

Endocrinology ◽

10.1210/en.2012-1152 ◽

2012 ◽

Vol 153 (7) ◽

pp. 3224-3235 ◽

Cited By ~ 56

Author(s):

Qiuli Fu ◽

Lies Gremeaux ◽

Raul M. Luque ◽

Daisy Liekens ◽

Jianghai Chen ◽

...

Keyword(s):

Pituitary Gland ◽

Progenitor Cells ◽

Transcriptional Activation ◽

Progenitor Cell ◽

Cell Activation ◽

Side Population ◽

Lineage Tracing ◽

Pituitary Cells ◽

Adult Age ◽

Gh Cells

The pituitary gland constitutes, together with the hypothalamus, the regulatory core of the endocrine system. Whether the gland is capable of cell regeneration after injury, in particular when suffered at adult age, is unknown. To investigate the adult pituitary's regenerative capacity and the response of its stem/progenitor cell compartment to damage, we constructed a transgenic mouse model to conditionally destroy pituitary cells. GHCre/iDTR mice express diphtheria toxin (DT) receptor after transcriptional activation by Cre recombinase, which is driven by the GH promoter. Treatment with DT for 3 d leads to gradual GH+ (somatotrope) cell obliteration with a final ablation grade of 80–90% 1 wk later. The stem/progenitor cell-clustering side population promptly expands after injury, concordant with the immediate increase in Sox2+ stem/progenitor cells. In addition, folliculo-stellate cells, previously designated as pituitary stem/progenitor cells and significantly overlapping with Sox2+ cells, also increase in abundance. In situ examination reveals expansion of the Sox2+ marginal-zone niche and appearance of remarkable Sox2+ cells that contain GH. When mice are left after the DT-provoked lesion, GH+ cells considerably regenerate during the following months. Double Sox2+/GH+ cells are observed throughout the regenerative period, suggesting recovery of somatotropes from stem/progenitor cells, as further supported by 5-ethynyl-2′-deoxyuridine (EdU) pulse-chase lineage tracing. In conclusion, our study demonstrates that the adult pituitary gland holds regenerative competence and that tissue repair follows prompt activation and plausible involvement of the stem/progenitor cells.

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Abstract 238: Role of Erythropoietin Signaling in the Biology of Mouse Cardiac Progenitor Cells

Circulation Research ◽

10.1161/res.111.suppl_1.a238 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Maria P Zafiriou ◽

Claudia Noack ◽

Michael Didie ◽

Bernhard Unsoeld ◽

Ali El-Armouche ◽

...

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

Cell Activation ◽

Ischemia Reperfusion ◽

Cardiac Cells ◽

Functional Improvement ◽

Cardiac Progenitor Cells ◽

Epor Expression

Erythropoietin (Epo) was shown to improve cardiac function following ischemia reperfusion mainly via neo-angiogenesis and anti-apoptotic mechanisms. We found EpoR expression to be particularly high in adult cardiac progenitor cells (CPCs). Thus, we reasoned that Epo may play a role in the biology of these cells. We isolated CPCs from adult C57BL/6 hearts by enzymatic digestion and filtration (pore size: 30 µm). By means of immunofluorescence microscopy (IF) and flow cytometry (FC) we analyzed EpoR expression in the CPCs. 24±3% of the investigated cardiac cells were positive for EpoR with 3±2% of these being c-kit+ and 28%±2% Sca-1+. 52% of the EpoR+ cells expressed endothelial cell markers (40±2% CD34+, 9±2% FLK1+). 42±4% expressed myocyte markers (αMHC+, cTNT+). IF revealed a progenitor-like population with immature cell morphology and proliferation potential (ki67+). Cell cycle analysis showed an enrichment of αMHC+ EpoR+ cells in S and G2 phase (49±7%, n=3) as compared to the αMHC- EpoR- population (13±3%, n=3). Moreover, we tested the effect of Epo in the biology of these CPCs in vitro. At d14 we observed a two-fold increase of GATA4+ and cTnT+ cardiac cells in the co-cultures treated with Epo (n=3). CPC cycle arrest abrogated the aforementioned effects, suggesting that Epo influences mainly CPC proliferation. Finally, we tested the potential of Epo to protect against ischemia by inducing the proliferation of these αMHC+ CPCs in vivo in a myocardial infarction (MI) model. 4 weeks post MI, echocardiography did not reveal a significant functional improvement of the Epo receiving mice (2x, 2U/g Epo i.p). Nevertheless, FC analysis of the progenitor pool showed a significant augmentation of αMHC+ and cTnT+ cells (Sham: 19±3% vs Epo 35±3%, n=5; MI: 10.6±2.3%, n=6 vs Epo 20.3±1.9%, n=8). These data suggest an activation of myogenic progenitors by Epo, despite the lack of apparent regeneration under the investigated conditions. In conclusion, we found that EpoR is expressed in a putative cardiomyogenic progenitor cell pool in the adult heart. Epo drives their proliferation in vitro and in vivo even upon acute cardiac injury. We are currently investigating the long-term consequences of the observed progenitor cell activation in models of chronic ischemic injury.

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miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations

International Journal of Molecular Sciences ◽

10.3390/ijms21031158 ◽

2020 ◽

Vol 21 (3) ◽

pp. 1158 ◽

Cited By ~ 2

Author(s):

Sarah C. Hoelscher ◽

Theresia Stich ◽

Anne Diehm ◽

Harald Lahm ◽

Martina Dreßen ◽

...

Keyword(s):

Pluripotent Stem Cells ◽

Heart Development ◽

Regulatory Networks ◽

Progenitor Cell ◽

Cardiac Development ◽

Loss Of Function ◽

And Function ◽

Cardiac Transcription Factors ◽

Beating Frequency

MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker Myl2 accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of Isl1, Sfrp5, Nkx2.5, and Mef2c, but increased Irx4, (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (Tnnt2+, Myh6+, Shox2+) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes.

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How Mesp1 makes a move

The Journal of Cell Biology ◽

10.1083/jcb.201604121 ◽

2016 ◽

Vol 213 (4) ◽

pp. 411-413 ◽

Cited By ~ 2

Author(s):

Robert G. Kelly

Keyword(s):

Transcription Factors ◽

Cell Migration ◽

Progenitor Cells ◽

Progenitor Cell ◽

Fate Specification ◽

Cell Biol ◽

Multipotent Progenitor Cells

The transcription factors Mesp1 and Mesp2 have essential roles in the migration and specification of multipotent progenitor cells at the onset of cardiogenesis. Chiapparo et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201505082) identify common Mesp functions in fate specification and Mesp1-specific targets controlling the speed and direction of progenitor cell migration.

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