Proliferation tracing reveals regional hepatocyte generation in liver homeostasis and repair

Science ◽  
2021 ◽  
Vol 371 (6532) ◽  
pp. eabc4346 ◽  
Author(s):  
Lingjuan He ◽  
Wenjuan Pu ◽  
Xiuxiu Liu ◽  
Zhenqian Zhang ◽  
Maoying Han ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Genetic System ◽  
Clonal Analysis ◽  
Lineage Tracing ◽  
Hepatocyte Proliferation ◽  
Cell Populations ◽  
Injury Repair ◽  
Multiple Organs ◽  
Entire Cell ◽  
Cellular Compartments

Organ homeostasis is orchestrated by time- and spatially restricted cell proliferation. Studies identifying cells with superior proliferative capacities often rely on the lineage tracing of a subset of cell populations, which introduces a potential selective bias. In this work, we developed a genetic system [proliferation tracer (ProTracer)] by incorporating dual recombinases to seamlessly record the proliferation events of entire cell populations over time in multiple organs. In the mouse liver, ProTracer revealed more hepatocyte proliferation in distinct zones during liver homeostasis, injury repair, and regrowth. Clonal analysis showed that most of the hepatocytes labeled by ProTracer had undergone cell division. By genetically recording proliferation events of entire cell populations, ProTracer enables the unbiased detection of specific cellular compartments with enhanced regenerative capacities.

Patches in the livers of chimaeric mice

Development ◽  
1976 ◽  
Vol 36 (1) ◽  
pp. 151-161
Author(s):  
J. D. West
Keyword(s):  
Clonal Analysis ◽  
Cell Populations ◽  
Adult Liver ◽  
One Dimensional ◽  
Glucuronidase Activity

Sections of adult chimaeric livers have been histochemically stained for β-glucuronidase activity and patches of two cell populations visualized. A one-dimensional clonal analysis has been used to estimate the number of coherent clones in the adult liver. The data are consistent with a total of 9–22 million regular, coherent clones, comprising 10–34 nuclei, or a smaller number of irregular, branched coherent clones. Both of these alternatives suggest considerable cell mixing during liver morphogenesis.

scholarly journals Extensive phylogenies of human development reveal variable embryonic patterns

2020 ◽  
Author(s):  
Tim H. H. Coorens ◽  
Luiza Moore ◽  
Philip S. Robinson ◽  
Rashesh Sanghvi ◽  
Joseph Christopher ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Spatial Effect ◽  
Lineage Tracing ◽  
Substantial Variation ◽  
Normal Tissues ◽  
Multiple Organs ◽  
Naturally Occurring ◽  
Adult Body ◽  
Laser Capture ◽  
Laser Capture Microdissected

ABSTRACTStarting from the zygote, all cells in the developing and adult human body continuously acquire mutations. A mutation shared between two different cells implies a shared progenitor cell and can thus be used as a naturally occurring marker for lineage tracing. Here, we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissected samples from multiple organs. Early embryonic progenitor cells inferred from the phylogenies often contribute in different proportions to the adult body and the extent of this asymmetry is variable between individuals, with ratios between the first two reconstructed cells ranging from 56:44 to 92:8. Asymmetries also pervade subsequent cell generations and can differ between tissues in the same individual. The phylogenies also resolve the spatial embryonic origins and patterning of tissues, revealing a spatial effect in the development of the human brain. Supplemented by data on eleven men, we timed the split between soma and germline, with the earliest observed segregation occurring at the first cell divisions. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

scholarly journals Lineage tracing reveals the hierarchical relationship between neural stem cell populations in the mouse forebrain

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nadia Sachewsky ◽  
Wenjun Xu ◽  
Tobias Fuehrmann ◽  
Derek van der Kooy ◽  
Cindi M. Morshead
Keyword(s):  
Neural Development ◽  
Lineage Tracing ◽  
Mammalian Brain ◽  
Cell Populations ◽  
Neural Repair ◽  
Hierarchical Relationship ◽  
Asymmetric Divisions ◽  
Stem Cell Populations ◽  
Adult Mammalian Brain

AbstractSince the original isolation of neural stem cells (NSCs) in the adult mammalian brain, further work has revealed a heterogeneity in the NSC pool. Our previous work characterized a distinct, Oct4 expressing, NSC population in the periventricular region, through development and into adulthood. We hypothesized that this population is upstream in lineage to the more abundant, well documented, GFAP expressing NSC. Herein, we show that Oct4 expressing NSCs give rise to neurons, astrocytes and oligodendrocytes throughout the developing brain. Further, transgenic inducible mouse models demonstrate that the rare Oct4 expressing NSCs undergo asymmetric divisions to give rise to GFAP expressing NSCs in naïve and injured brains. This lineage relationship between distinct NSC pools contributes significantly to an understanding of neural development, the NSC lineage in vivo and has implications for neural repair.

scholarly journals Increasing the Content of High-Content Screening

2014 ◽  
Vol 19 (5) ◽  
pp. 640-650 ◽  
Author(s):  
Shantanu Singh ◽  
Anne E. Carpenter ◽  
Auguste Genovesio
Keyword(s):  
Data Analysis ◽  
High Throughput Screening ◽  
High Content Screening ◽  
Cell Populations ◽  
Phenotypic Screening ◽  
Data Sets ◽  
Phenotypic Information ◽  
Entire Cell ◽  
Data Analysis Methods ◽  
Screening Approaches

Target-based high-throughput screening (HTS) has recently been critiqued for its relatively poor yield compared to phenotypic screening approaches. One type of phenotypic screening, image-based high-content screening (HCS), has been seen as particularly promising. In this article, we assess whether HCS is as high content as it can be. We analyze HCS publications and find that although the number of HCS experiments published each year continues to grow steadily, the information content lags behind. We find that a majority of high-content screens published so far (60−80%) made use of only one or two image-based features measured from each sample and disregarded the distribution of those features among each cell population. We discuss several potential explanations, focusing on the hypothesis that data analysis traditions are to blame. This includes practical problems related to managing large and multidimensional HCS data sets as well as the adoption of assay quality statistics from HTS to HCS. Both may have led to the simplification or systematic rejection of assays carrying complex and valuable phenotypic information. We predict that advanced data analysis methods that enable full multiparametric data to be harvested for entire cell populations will enable HCS to finally reach its potential.

scholarly journals DNA barcode-guided lentiviral CRISPRa tool to trace and isolate individual clonal lineages in heterogeneous cancer cell populations

2019 ◽  
Author(s):  
Y Akimov ◽  
D Bulanova ◽  
M Abyzova ◽  
K Wennerberg ◽  
T Aittokallio
Keyword(s):  
Dna Barcoding ◽  
Cancer Cell ◽  
Experimental Evaluation ◽  
System Performance ◽  
Dna Barcode ◽  
Lineage Tracing ◽  
Cell Populations ◽  
Functional Heterogeneity ◽  
High Complexity ◽  
Cell Lineages

AbstractThe genetic and functional heterogeneity of tumors imposes the challenge of understanding how a cancer progresses, evolves and adapts to treatment at the subclonal level. Therefore, there is a critical need for methods that enable profiling of individual cancer cell lineages. Here, we report a novel system that couples an established DNA barcoding technique for lineage tracing with a controlled DNA barcode-guided lineage isolation (B-GLI). B-GLI allows both high-complexity of lineage tracing and effective isolation of individual clones by CRISPRa-mediated induction of puromycin resistance, making it possible to unbiasedly trace, isolate, and study individual cancer cell lineages. We present experimental evaluation of the system performance in isolation of lineages and outline a comprehensive workflow for B-GLI applications. We believe the system has broad applications aimed at molecular and phenotypic profiling of individual lineages in heterogeneous cell populations.

scholarly journals Lineage Tracing and Clonal Analysis in Developing Cerebral Cortex Using Mosaic Analysis with Double Markers (MADM)

10.3791/61147 ◽  
2020 ◽  
Author(s):  
Robert Beattie ◽  
Carmen Streicher ◽  
Nicole Amberg ◽  
Giselle Cheung ◽  
Ximena Contreras ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Clonal Analysis ◽  
Lineage Tracing ◽  
Mosaic Analysis

scholarly journals Retinoic acid signaling is directly activated in cardiomyocytes and protects mouse hearts from apoptosis after myocardial infarction

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Fabio Da Silva ◽  
Fariba Jian Motamedi ◽  
Lahiru Chamara Weerasinghe Arachchige ◽  
Amelie Tison ◽  
Stephen T Bradford ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Retinoic Acid ◽  
Cardiac Development ◽  
Protective Role ◽  
Lineage Tracing ◽  
Late Gestation ◽  
Sequencing Analysis ◽  
Cell Type ◽  
Multiple Organs ◽  
Genes Encoding

Retinoic acid (RA) is an essential signaling molecule for cardiac development and plays a protective role in the heart after myocardial infarction (MI). In both cases, the effect of RA signaling on cardiomyocytes, the principle cell type of the heart, has been reported to be indirect. Here we have developed an inducible murine transgenic RA-reporter line using CreERT2 technology that permits lineage tracing of RA-responsive cells and faithfully recapitulates endogenous RA activity in multiple organs during embryonic development. Strikingly, we have observed a direct RA response in cardiomyocytes during mid-late gestation and after MI. Ablation of RA signaling through deletion of the Aldh1a1/a2/a3 genes encoding RA-synthesizing enzymes leads to increased cardiomyocyte apoptosis in adults subjected to MI. RNA sequencing analysis reveals Tgm2 and Ace1, two genes with well-established links to cardiac repair, as potential targets of RA signaling in primary cardiomyocytes, thereby providing novel links between the RA pathway and heart disease.

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