scholarly journals Putative oncogene Brachyury (T) is essential to specify cell fate but dispensable for notochord progenitor proliferation and EMT

2016 ◽  
Vol 113 (14) ◽  
pp. 3820-3825 ◽  
Author(s):  
Jianjian Zhu ◽  
Kin Ming Kwan ◽  
Susan Mackem
Keyword(s):  
Cell Fate ◽  
Epithelial Mesenchymal Transition ◽  
Primitive Streak ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Mesenchymal Transition ◽  
Neural Fate ◽  
Notochord Cell ◽  
Genetic Lineage Tracing ◽  
And Function

The transcription factor Brachyury (T) gene is expressed throughout primary mesoderm (primitive streak and notochord) during early embryonic development and has been strongly implicated in the genesis of chordoma, a sarcoma of notochord cell origin. Additionally, T expression has been found in and proposed to play a role in promoting epithelial–mesenchymal transition (EMT) in various other types of human tumors. However, the role of T in normal mammalian notochord development and function is still not well-understood. We have generated an inducible knockdown model to efficiently and selectively deplete T from notochord in mouse embryos. In combination with genetic lineage tracing, we show that T function is essential for maintaining notochord cell fate and function. Progenitors adopt predominantly a neural fate in the absence of T, consistent with an origin from a common chordoneural progenitor. However, T function is dispensable for progenitor cell survival, proliferation, and EMT, which has implications for the therapeutic targeting of T in chordoma and other cancers.

scholarly journals Ventricular, atrial and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

2020 ◽  
Author(s):  
Kenzo Ivanovitch ◽  
Pablo Soro-Barrio ◽  
Probir Chakravarty ◽  
Rebecca A Jones ◽  
S. Neda Mousavy Gharavy ◽  
...  
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Primitive Streak ◽  
Outflow Tract ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Cardiac Progenitors ◽  
Heart Field ◽  
Genetic Lineage Tracing

AbstractThe heart develops from two sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single cell transcriptomic assay in combination with genetic lineage tracing, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are pre-patterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function and disease.

scholarly journals Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001200
Author(s):  
Kenzo Ivanovitch ◽  
Pablo Soro-Barrio ◽  
Probir Chakravarty ◽  
Rebecca A. Jones ◽  
Donald M. Bell ◽  
...  
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Primitive Streak ◽  
Outflow Tract ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Cardiac Progenitors ◽  
Heart Field ◽  
Genetic Lineage Tracing

The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.

scholarly journals Cell Specific Reactivation of Epicardium at the Origin of Fibro-Fatty Remodeling of the Atrial Myocardium

2019 ◽  
Author(s):  
Nadine Suffee ◽  
Thomas Moore-Morris ◽  
Nathalie Mougenot ◽  
Gilles Dilanian ◽  
Myriam Berthet ◽  
...  
Keyword(s):  
Cell Fate ◽  
Fatty Infiltration ◽  
Lineage Tracing ◽  
Atrial Remodeling ◽  
Genetic Lineage ◽  
Specific Cell ◽  
Rna Seq ◽  
Aged Patients ◽  
Multipotent Cells ◽  
Genetic Lineage Tracing

AbstractEpicardium, the mesothelium covering the heart, is composed of multipotent cells and is reactivated following myocardial injury in adults. Herein, we provide evidence for activation of atrial epicardium in aged patients with diseased atria and in murine models of atrial remodeling. Epicardial activation contributed to fibro-fatty infiltration of sub-epicardium that contained a number of cells co-expressing markers of epicardial progenitors and fibroblasts. Indeed, using genetic lineage tracing of adult epicardium, we demonstrate the epicardial origin of fibroblasts within fibro-fatty infiltrates. A subpopulation of adult epicardial-derived cells (aEPDCs) expressing PDGFRα, niched in the sub-epicardium, were isolated and differentiated into myofibroblast in the presence of angiotensin-II. Furthermore, single cell RNA-seq analysis identified several clusters of aEPDCs and revealed transition from adipogenic to fibrogenic cells. In conclusion, a subset of aEPDCs, pre-programmed towards a specific cell fate, contributes to fibro-fatty infiltration of sub-epicardium of diseased atria.

scholarly journals Fibroblast State Reversal By MBNL1-Dependent Transcriptome Modification Regulates Cardiac Repair

2021 ◽  
Author(s):  
Darrian Bugg ◽  
Ross Bretherton ◽  
Kylie Beach ◽  
Anna Reese ◽  
Jagadambika Gunaje ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
State Transition ◽  
Rna Binding ◽  
Cardiac Fibroblasts ◽  
Lineage Tracing ◽  
State Transitions ◽  
Genetic Lineage ◽  
Fibrotic Response ◽  
Mesenchymal Transition ◽  
Genetic Lineage Tracing

SUMMARYDynamic fibroblast state transitions are responsible for the heart’s fibrotic response to injury, raising the possibility that tactical control of these transitions could alter maladaptive fibrotic outcomes. Transcriptome maturation by the RNA binding protein Muscleblind Like 1 (MBNL1) has emerged as a potential driver of differentiated cell states. Here genetic lineage tracing of myofibroblasts in the injured heart demonstrated that gains in MBNL1 function corresponded to profibrotic fibroblast states. Similarly, in mice cardiac fibroblast specific MBNL1 overexpression induced a transcriptional myofibroblast profile in healthy cardiac fibroblasts that prevented the fibroproliferative phase of cardiac wound healing. By contrast loss of MBNL1 reverted cardiac fibroblasts to a pro-proliferative epicardial progenitor state that limited cardiac fibrosis following myocardial infarction. This progenitor state transition was associated with an MBNL1-dependent destabilization of the mesenchymal transition gene, Sox9. These findings suggest that MBNL1 regulation of the fibroblast transcriptome drives state transitions underlying cardiac fibrosis and repair.

scholarly journals Signalling codes for the maintenance and lineage commitment of embryonic gastric epithelial progenitors

Development ◽  
2020 ◽  
Vol 147 (18) ◽  
pp. dev188839
Author(s):  
Sergi Sayols ◽  
Jakub Klassek ◽  
Clara Werner ◽  
Stefanie Möckel ◽  
Sandra Ritz ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Fate ◽  
Ex Vivo ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Gastric Epithelium ◽  
Genetic Lineage ◽  
Genetic Lineage Tracing ◽  
Notch Pathways

ABSTRACTThe identity of embryonic gastric epithelial progenitors is unknown. We used single-cell RNA-sequencing, genetic lineage tracing and organoid assays to assess whether Axin2- and Lgr5-expressing cells are gastric progenitors in the developing mouse stomach. We show that Axin2+ cells represent a transient population of embryonic epithelial cells in the forestomach. Lgr5+ cells generate both glandular corpus and squamous forestomach organoids ex vivo. Only Lgr5+ progenitors give rise to zymogenic cells in culture. Modulating the activity of the WNT, BMP and Notch pathways in vivo and ex vivo, we found that WNTs are essential for the maintenance of Lgr5+ epithelial cells. Notch prevents differentiation of the embryonic epithelial cells along all secretory lineages and hence ensures their maintenance. Whereas WNTs promote differentiation of the embryonic progenitors along the zymogenic cell lineage, BMPs enhance their differentiation along the parietal lineage. In contrast, WNTs and BMPs are required to suppress differentiation of embryonic gastric epithelium along the pit cell lineage. Thus, coordinated action of the WNT, BMP and Notch pathways controls cell fate determination in the embryonic gastric epithelium.

scholarly journals Genetic lineage tracing with multiple DNA recombinases: A user's guide for conducting more precise cell fate mapping studies

2020 ◽  
Vol 295 (19) ◽  
pp. 6413-6424 ◽  
Author(s):  
Kuo Liu ◽  
Hengwei Jin ◽  
Bin Zhou
Keyword(s):  
Cell Fate ◽  
Cell Biology ◽  
Lineage Tracing ◽  
Cell Labeling ◽  
Genetic Lineage ◽  
Fate Mapping ◽  
Technical Limitation ◽  
Biological Phenomena ◽  
Recombination System ◽  
Genetic Lineage Tracing

Site-specific recombinases, such as Cre, are a widely used tool for genetic lineage tracing in the fields of developmental biology, neural science, stem cell biology, and regenerative medicine. However, nonspecific cell labeling by some genetic Cre tools remains a technical limitation of this recombination system, which has resulted in data misinterpretation and led to many controversies in the scientific community. In the past decade, to enhance the specificity and precision of genetic targeting, researchers have used two or more orthogonal recombinases simultaneously for labeling cell lineages. Here, we review the history of cell-tracing strategies and then elaborate on the working principle and application of a recently developed dual genetic lineage-tracing approach for cell fate studies. We place an emphasis on discussing the technical strengths and caveats of different methods, with the goal to develop more specific and efficient tracing technologies for cell fate mapping. Our review also provides several examples for how to use different types of DNA recombinase–mediated lineage-tracing strategies to improve the resolution of the cell fate mapping in order to probe and explore cell fate–related biological phenomena in the life sciences.

scholarly journals Visualization of stem cell activity in pancreatic cancer expansion by direct lineage tracing with live imaging

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Takahisa Maruno ◽  
Akihisa Fukuda ◽  
Norihiro Goto ◽  
Motoyuki Tsuda ◽  
Kozo Ikuta ◽  
...  
Keyword(s):  
Stem Cell ◽  
Epithelial Mesenchymal Transition ◽  
Cell Activity ◽  
Live Imaging ◽  
Lineage Tracing ◽  
Ductal Adenocarcinoma ◽  
Genetic Lineage ◽  
Mesenchymal Transition ◽  
Stem Cell Activity

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of ‘cancer stem cells (CSCs)’ in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1+ tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1+ and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1+ cells in vivo, revealing the essential roles of Dclk1+ cells in expansion of pancreatic neoplasia in all progressive stages.

scholarly journals Genetic lineage tracing defines myofibroblast origin and function in the injured heart

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Onur Kanisicak ◽  
Hadi Khalil ◽  
Malina J. Ivey ◽  
Jason Karch ◽  
Bryan D. Maliken ◽  
...  
Keyword(s):  
Lineage Tracing ◽  
Genetic Lineage ◽  
Genetic Lineage Tracing ◽  
And Function

scholarly journals Hepatocyte generation in liver homeostasis, repair, and regeneration

2022 ◽  
Vol 11 (1) ◽  
Author(s):  
Wenjuan Pu ◽  
Bin Zhou
Keyword(s):  
Cell Fate ◽  
Tissue Regeneration ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Cellular Reprogramming ◽  
Hepatocyte Proliferation ◽  
Genetic Lineage ◽  
Regenerative Capacity ◽  
The Past ◽  
Genetic Lineage Tracing

AbstractThe liver has remarkable capability to regenerate, employing mechanism to ensure the stable liver-to-bodyweight ratio for body homeostasis. The source of this regenerative capacity has received great attention over the past decade yet still remained controversial currently. Deciphering the sources for hepatocytes provides the basis for understanding tissue regeneration and repair, and also illustrates new potential therapeutic targets for treating liver diseases. In this review, we describe recent advances in genetic lineage tracing studies over liver stem cells, hepatocyte proliferation, and cell lineage conversions or cellular reprogramming. This review will also evaluate the technical strengths and limitations of methods used for studies on hepatocyte generation and cell fate plasticity in liver homeostasis, repair and regeneration.

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