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.

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 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 Tracing epithelial stem cells during development, homeostasis, and repair

2012 ◽  
Vol 197 (5) ◽  
pp. 575-584 ◽  
Author(s):  
Alexandra Van Keymeulen ◽  
Cédric Blanpain
Keyword(s):  
Stem Cells ◽  
Tissue Regeneration ◽  
External Environment ◽  
Lineage Tracing ◽  
The Body ◽  
Genetic Lineage ◽  
Epithelial Stem Cells ◽  
Differentiation Potential ◽  
Physiological Conditions ◽  
Genetic Lineage Tracing

Epithelia ensure many critical functions of the body, including protection against the external environment, nutrition, respiration, and reproduction. Stem cells (SCs) located in the various epithelia ensure the homeostasis and repair of these tissues throughout the lifetime of the animal. Genetic lineage tracing in mice has allowed the labeling of SCs and their progeny. This technique has been instrumental in characterizing the origin and heterogeneity of epithelial SCs, their tissue location, and their differentiation potential under physiological conditions and during tissue regeneration.

scholarly journals Nkx2.5 marks angioblasts that contribute to hemogenic endothelium of the endocardium and dorsal aorta

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Lyad Zamir ◽  
Reena Singh ◽  
Elisha Nathan ◽  
Ralph Patrick ◽  
Oren Yifa ◽  
...  
Keyword(s):  
Temporal Dynamics ◽  
Ectopic Expression ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Dorsal Aorta ◽  
Genetic Lineage ◽  
Hemogenic Endothelium ◽  
Lateral Plate ◽  
Spatio Temporal ◽  
Genetic Lineage Tracing

Novel regenerative therapies may stem from deeper understanding of the mechanisms governing cardiovascular lineage diversification. Using enhancer mapping and live imaging in avian embryos, and genetic lineage tracing in mice, we investigated the spatio-temporal dynamics of cardiovascular progenitor populations. We show that expression of the cardiac transcription factor Nkx2.5 marks a mesodermal population outside of the cardiac crescent in the extraembryonic and lateral plate mesoderm, with characteristics of hemogenic angioblasts. Extra-cardiac Nkx2.5 lineage progenitors migrate into the embryo and contribute to clusters of CD41+/CD45+ and RUNX1+ cells in the endocardium, the aorta-gonad-mesonephros region of the dorsal aorta and liver. We also demonstrated that ectopic expression of Nkx2.5 in chick embryos activates the hemoangiogenic gene expression program. Taken together, we identified a hemogenic angioblast cell lineage characterized by transient Nkx2.5 expression that contributes to hemogenic endothelium and endocardium, suggesting a novel role for Nkx2.5 in hemoangiogenic lineage specification and diversification.

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 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 Cellular origins and lineage relationships of the intestinal epithelium

2021 ◽  
Author(s):  
Claudia Capdevila ◽  
Maria Trifas ◽  
Jonathan Miller ◽  
Troy Anderson ◽  
Peter A. Sims ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Developmental Trajectories ◽  
Cell Lineage ◽  
Cell Types ◽  
Lineage Tracing ◽  
Hierarchical Organization ◽  
Genetic Lineage ◽  
Intestinal Epithelial ◽  
Lineage Specification ◽  
Genetic Lineage Tracing

Knowledge of the development and hierarchical organization of tissues is key to understanding how they are perturbed in injury and disease, as well as how they may be therapeutically manipulated to restore homeostasis. The rapidly regenerating intestinal epithelium harbors diverse cell types and their lineage relationships have been studied using numerous approaches, from classical label-retaining and genetic lineage tracing methods to novel transcriptome-based annotations. Here, we describe the developmental trajectories that dictate differentiation and lineage specification in the intestinal epithelium. We focus on the most recent single-cell RNA-sequencing (scRNA-seq)-based strategies for understanding intestinal epithelial cell lineage relationships, underscoring how they have refined our view of the development of this tissue and highlighting their advantages and limitations. We emphasize how these technologies have been applied to understand the dynamics of intestinal epithelial cells in homeostatic and injury-induced regeneration models.

scholarly journals The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Guillermo Rodríguez-Hernández ◽  
Ana Casado-García ◽  
Marta Isidro-Hernández ◽  
Daniel Picard ◽  
Javier Raboso-Gallego ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Fate ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Gene Expression Profiles ◽  
Genetic Alterations ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Second Hit

ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies.

scholarly journals Epithelial Cell Lineage and Signaling in Murine Salivary Glands

2019 ◽  
Vol 98 (11) ◽  
pp. 1186-1194 ◽  
Author(s):  
M.H. Aure ◽  
J.M. Symonds ◽  
J.W. Mays ◽  
M.P. Hoffman
Keyword(s):  
Salivary Gland ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Cell Lineage ◽  
Cell Types ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Recent Advances ◽  
Epithelial Development ◽  
Gland Development

Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren’s syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.

scholarly journals Triple-cell lineage tracing by a dual reporter on a single allele

2019 ◽  
Vol 295 (3) ◽  
pp. 690-700 ◽  
Author(s):  
Kuo Liu ◽  
Muxue Tang ◽  
Hengwei Jin ◽  
Qiaozhen Liu ◽  
Lingjuan He ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Cell Function ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Cell Populations ◽  
Genetic Lineage ◽  
Traffic Light ◽  
Reporter System

Genetic lineage tracing is widely used to study organ development and tissue regeneration. Multicolor reporters are a powerful platform for simultaneously tracking discrete cell populations. Here, combining Dre-rox and Cre-loxP systems, we generated a new dual-recombinase reporter system, called Rosa26 traffic light reporter (R26-TLR), to monitor red, green, and yellow fluorescence. Using this new reporter system with the three distinct fluorescent reporters combined on one allele, we found that the readouts of the two recombinases Cre and Dre simultaneously reflect Cre+Dre−, Cre−Dre+, and Cre+Dre+ cell lineages. As proof of principle, we show specific labeling in three distinct progenitor/stem cell populations, including club cells, AT2 cells, and bronchoalveolar stem cells, in Sftpc-DreER;Scgb1a1-CreER;R26-TLR mice. By using this new dual-recombinase reporter system, we simultaneously traced the cell fate of these three distinct cell populations during lung repair and regeneration, providing a more comprehensive picture of stem cell function in distal airway repair and regeneration. We propose that this new reporter system will advance developmental and regenerative research by facilitating a more sophisticated genetic approach to studying in vivo cell fate plasticity.

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