scholarly journals Taking a Step Back: Insights into the Mechanisms Regulating Gut Epithelial Dedifferentiation

2021 ◽  
Vol 22 (13) ◽  
pp. 7043
Author(s):  
Shaida Ouladan ◽  
Alex Gregorieff
Keyword(s):  
Cell Fate ◽  
Hormonal Regulation ◽  
Transcriptional Profiling ◽  
Cell Types ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Physical Damage ◽  
Epithelial Regeneration ◽  
Gut Epithelium ◽  
Stem Cell Populations

Despite the environmental constraints imposed upon the intestinal epithelium, this tissue must perform essential functions such as nutrient absorption and hormonal regulation, while also acting as a critical barrier to the outside world. These functions depend on a variety of specialized cell types that are constantly renewed by a rapidly proliferating population of intestinal stem cells (ISCs) residing at the base of the crypts of Lieberkühn. The niche components and signals regulating crypt morphogenesis and maintenance of homeostatic ISCs have been intensely studied over the last decades. Increasingly, however, researchers are turning their attention to unraveling the mechanisms driving gut epithelial regeneration due to physical damage or infection. It is now well established that injury to the gut barrier triggers major cell fate changes, demonstrating the highly plastic nature of the gut epithelium. In particular, lineage tracing and transcriptional profiling experiments have uncovered several injury-induced stem-cell populations and molecular markers of the regenerative state. Despite the progress achieved in recent years, several questions remain unresolved, particularly regarding the mechanisms driving dedifferentiation of the gut epithelium. In this review, we summarize the latest studies, primarily from murine models, that define the regenerative processes governing the gut epithelium and discuss areas that will require more in-depth investigation.

scholarly journals Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells

2010 ◽  
Vol 108 (1) ◽  
pp. 179-184 ◽  
Author(s):  
Robert K. Montgomery ◽  
Diana L. Carlone ◽  
Camilla A. Richmond ◽  
Loredana Farilla ◽  
Mariette E. G. Kranendonk ◽  
...  
Keyword(s):  
Stem Cells ◽  
Reverse Transcriptase ◽  
Tissue Injury ◽  
Cell Types ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Intestinal Cell ◽  
Stem Cell Population ◽  
Telomerase Reverse Transcriptase

The intestinal epithelium is maintained by a population of rapidly cycling (Lgr5+) intestinal stem cells (ISCs). It has been postulated, however, that slowly cycling ISCs must also be present in the intestine to protect the genome from accumulating deleterious mutations and to allow for a response to tissue injury. Here, we identify a subpopulation of slowly cycling ISCs marked by mouse telomerase reverse transcriptase (mTert) expression that can give rise to Lgr5+ cells. mTert-expressing cells distribute in a pattern along the crypt–villus axis similar to long-term label-retaining cells (LRCs) and are resistant to tissue injury. Lineage-tracing studies demonstrate that mTert+ cells give rise to all differentiated intestinal cell types, persist long term, and contribute to the regenerative response following injury. Consistent with other highly regenerative tissues, our results demonstrate that a slowly cycling stem cell population exists within the intestine.

scholarly journals Tfap2b specifies an embryonic melanocyte stem cell population that retains adult multi-fate potential

2021 ◽  
Author(s):  
Alessandro Brombin ◽  
Daniel J. Simpson ◽  
Jana Travnickova ◽  
Hannah R. Brunsdon ◽  
Zhiqiang Zeng ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neural Crest ◽  
Pigment Cell ◽  
Cell Types ◽  
Lineage Tracing ◽  
Stem Cell Population ◽  
Cell Of Origin ◽  
Lineage Markers ◽  
Melanocyte Stem Cell ◽  
Stem Cell Populations

Melanocytes, our pigment producing cells, originate from neural crest-derived progenitors during embryogenesis and from multiple stem cell niches in adult tissues. Although pigmentation traits are known risk-factors for melanoma, we lack lineage markers with which to identify melanocyte stem cell populations and study their function. Here, by combining live-imaging, scRNA-seq and chemical-genetics in zebrafish, we identify the transcription factor Tfap2b as a functional marker for the melanocyte stem cell (MSC) population that resides at the dorsal root ganglia site. Tfap2b is required for only a few late-stage embryonic melanocytes, and instead is essential for MSC-dependent melanocyte regeneration. Our lineage-tracing data reveal that tfap2b-expressing MSCs have multi-fate potential, and are the cell-of-origin for a discrete number of embryonic melanocytes, large patches of adult melanocytes, and two other pigment cell types; iridophores and xanthophores. Hence, Tfap2b confers MSC identity, and thereby distinguishes MSCs from other neural crest and pigment cell lineages.

scholarly journals Conservation and Divergence of YODA MAPKKK Function in Regulation of Grass Epidermal Patterning

2018 ◽  
Author(s):  
Emily Abrash ◽  
M Ximena Anleu Gil ◽  
Juliana L Matos ◽  
Dominique C Bergmann
Keyword(s):  
Cell Fate ◽  
Cell Types ◽  
Lineage Tracing ◽  
Cell Fates ◽  
Kinase Gene ◽  
Asymmetric Cell Divisions ◽  
Cell Divisions ◽  
Asymmetric Divisions ◽  
Species Specific ◽  
Multicellular Organisms

AbstractAll multicellular organisms must properly pattern cell types to generate functional tissues and organs. The organized and predictable cell lineages of the Brachypodium leaf enabled us to characterize the role of the MAPK kinase kinase gene BdYODA1 in regulating asymmetric cell divisions. We find that YODA genes promote normal stomatal spacing patterns in both Arabidopsis and Brachypodium, despite species-specific differences in those patterns. Using lineage tracing and cell fate markers, we show that, unexpectedly, patterning defects in bdyoda1 mutants do not arise from faulty physical asymmetry in cell divisions but rather from improper enforcement of alternative cellular fates after division. These cross-species comparisons allow us to refine our interpretations of MAPK activities during plant asymmetric cell divisions.Summary StatementAnalysis of Brachypodium leaf epidermis development reveals that the MAPKKK, BdYODA1, regulates asymmetric divisions by enforcing resultant cell fates rather than driving initial physical asymmetries.

scholarly journals Neural crest lineage analysis: from past to future trajectory

Development ◽  
2020 ◽  
Vol 147 (20) ◽  
pp. dev193193 ◽  
Author(s):  
Weiyi Tang ◽  
Marianne E. Bronner
Keyword(s):  
Neural Crest ◽  
Cell Fate ◽  
Single Molecule ◽  
Cell Lineage ◽  
Neural Crest Cell ◽  
Cell Types ◽  
Lineage Tracing ◽  
Migration Routes ◽  
Developmental Potential ◽  
Lineage Analysis

ABSTRACTSince its discovery 150 years ago, the neural crest has intrigued investigators owing to its remarkable developmental potential and extensive migratory ability. Cell lineage analysis has been an essential tool for exploring neural crest cell fate and migration routes. By marking progenitor cells, one can observe their subsequent locations and the cell types into which they differentiate. Here, we review major discoveries in neural crest lineage tracing from a historical perspective. We discuss how advancing technologies have refined lineage-tracing studies, and how clonal analysis can be applied to questions regarding multipotency. We also highlight how effective progenitor cell tracing, when combined with recently developed molecular and imaging tools, such as single-cell transcriptomics, single-molecule fluorescence in situ hybridization and high-resolution imaging, can extend the scope of neural crest lineage studies beyond development to regeneration and cancer initiation.

scholarly journals Zebrafish pigment cells develop directly from persistent highly multipotent progenitors.

2021 ◽  
Author(s):  
Masataka Nikaido ◽  
Tatiana Subkhankulova ◽  
Leonid A. Uroshlev ◽  
Artem J. Kasianov ◽  
Karen Camargo Sosa ◽  
...  
Keyword(s):  
Pigment Cell ◽  
Transcriptional Profiling ◽  
Cell Types ◽  
Cell Development ◽  
Lineage Tracing ◽  
Pigment Cells ◽  
Multipotent Stem Cells ◽  
Multipotent Progenitors ◽  
Fate Restriction

Neural crest cells (NCCs) are highly multipotent stem cells. A long-standing controversy exists over the mechanism of NCC fate specification, specifically regarding the presence and potency of intermediate progenitors. The direct fate restriction (DFR) model, based on early in vivo clonal studies, hypothesised that intermediates are absent and that migrating cells maintain full multipotency. However, most authors favour progressive fate restriction (PFR) models, with fully multipotent early NCCs (ENCCs) transitioning to partially-restricted intermediates before committing to individual fates. Here, single cell transcriptional profiling of zebrafish pigment cell development leads to us proposing a Cyclical Fate Restriction mechanism of NCC development that reconciles the DFR and PFR models. Our clustering of single NCC Nanostring transcriptional profiles identifies only broadly multipotent intermediate states between ENCCs and differentiated melanocytes and iridophores. Leukocyte tyrosine kinase (Ltk) marks the multipotent progenitor and iridophores, consistent with biphasic ltk expression. Ltk inhibitor and constitutive activation studies support expression at an early multipotent stage, whilst lineage-tracing of ltk-expressing cells reveals their multipotency extends beyond pigment cell-types to neural fates. We conclude that pigment cell development does not involve a conventional PFR mechanism, but instead occurs directly and more dynamically from a broadly multipotent intermediate state.

scholarly journals Lineage tracing of Notch1-expressing cells in intestinal tumours reveals a distinct population of cancer stem cells

2018 ◽  
Author(s):  
Larissa Mourao ◽  
Guillaume Jacquemin ◽  
Mathilde Huyghe ◽  
Wojciech J. Nawrocki ◽  
Naoual Menssouri ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Critical Role ◽  
Tumour Cells ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Cellular Targets ◽  
Transcriptional Signature ◽  
Stem Cell Populations ◽  
Notch1 Receptor

AbstractColon tumours are hierarchically organized and contain multipotent self-renewing cells, called Cancer Stem Cells (CSCs). We have previously shown that the Notch1 receptor is expressed in Intestinal Stem Cells (ISCs); given the critical role played by Notch signalling in promoting intestinal tumourigenesis, we explored Notch1 expression in tumours. Combining lineage tracing in two tumour models with transcriptomic analyses, we found that Notch1 + tumour cells are undifferentiated, proliferative and capable of indefinite self-renewal and of generating a heterogeneous clonal progeny. Molecularly, the transcriptional signature of Notch1+ tumour cells highly correlates with ISCs, suggestive of their origin from normal crypt cells. Surprisingly, Notch1+ expression labels a subset of CSCs that show reduced levels of Lgr5, a reported CSCs marker. The existence of distinct stem cell populations within intestinal tumours highlights the necessity of better understanding their hierarchy and behaviour, to identify the correct cellular targets for therapy.

scholarly journals Re-entry into mitosis and regeneration of intestinal stem cells through enteroblast dedifferentiation in Drosophila midguts

2021 ◽  
Author(s):  
Aiguo Tian ◽  
Virginia Morejon ◽  
Sarah Kohoutek ◽  
Yi-Chun Huang ◽  
Wu-Min Deng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pathogenic Bacteria ◽  
Growth Factor Receptor ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Stem Cell Marker ◽  
Secretory Cells ◽  
Ras Signaling ◽  
Epithelial Regeneration ◽  
Resident Stem Cells

Many adult tissues and organs including the intestine rely on resident stem cells to maintain homeostasis. In mammalian intestines, upon ablation of resident stem cells, the progenies of intestinal stem cells (ISCs) such as secretory cells and tuft cells can dedifferentiate to generate ISCs to drive epithelial regeneration, but whether and how the ISC progenies dedifferentiate to generate ISCs under physiological conditions remains unknown. Here we show that infection of pathogenic bacteria induces enteroblasts (EBs) as one type of ISC progenies to re-enter the mitotic cycle in the Drosophila intestine. The re-entry into mitosis is dependent on epithermal growth factor receptor (EGFR)-Ras signaling and ectopic activation of EGFR-Ras signaling in EBs is sufficient to drive EBs cell-autonomously to re-enter into mitosis. In addition, we examined whether EBs gain ISC identity as a prerequisite to divide, but the immunostaining with stem cell marker Delta shows that these dividing EBs do not gain ISC identity. After employing lineage tracing experiments, we further demonstrate that EBs dedifferentiate to generate functional ISCs after symmetric divisions of EBs. Together, our study in Drosophila intestines uncovers a new role of EGFR-Ras signaling in regulating re-entry into mitosis and dedifferentiation during regeneration and reveals a novel mechanism by which ISC progenies undergo dedifferentiation through a mitotic division, which has important implication to mammalian tissue homeostasis and tumorigenesis.

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 Lineage recording of zebrafish embryogenesis reveals historical and ongoing lineage commitments

2020 ◽  
Author(s):  
Zhuoxin Chen ◽  
Chang Ye ◽  
Zhan Liu ◽  
Shanjun Deng ◽  
Xionglei He ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Cell Lineage ◽  
Cell Types ◽  
Lineage Tracing ◽  
Cell Type ◽  
Single Cell Sequencing ◽  
Sequencing Technologies ◽  
Development And Differentiation ◽  
Zebrafish Embryogenesis

AbstractIt has been challenging to characterize the lineage relationships among cells in vertebrates, which comprise a great number of cells. Fortunately, recent progress has been made by combining the CRISPR barcoding system with single-cell sequencing technologies to provide an unprecedented opportunity to track lineage at single-cell resolution. However, due to errors and/or dropouts introduced by amplification and sequencing, reconstruction of accurate lineage relationships in complex organisms remains a challenge. Thus, improvements in both experimental design and computational analysis are necessary for lineage inference. In this study, we employed single-cell Lineage tracing On Endogenous Scarring Sites (scLOESS), a lineage recording strategy based on the CRISPR-Cas9 system, to trace cell fate commitments for zebrafish larvae. With rigorous quality control, we demonstrated that lineage commitments of complex organisms could be inferred from a limited number of barcoding sites. Together with cell-type characterization, our method could homogenously recover lineage information. In combination with the cell-type and lineage information, we depicted the development histories for germ layers as well as cell types. Furthermore, when combined with trajectory analysis, our methods could capture and resolve the ongoing lineage commitment events to gain further biological insights into later development and differentiation in complex organisms.

scholarly journals Clonal analysis and dynamic imaging identify multipotency of individual Gallus gallus caudal hindbrain neural crest cells toward cardiac and enteric fates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weiyi Tang ◽  
Yuwei Li ◽  
Ang Li ◽  
Marianne E. Bronner
Keyword(s):  
Neural Crest ◽  
Single Cell ◽  
Cell Fate ◽  
Neural Crest Cells ◽  
Time Lapse ◽  
Cell Types ◽  
Clonal Analysis ◽  
Dynamic Imaging ◽  
Lineage Tracing ◽  
Enteric Ganglia

AbstractNeural crest stem cells arising from caudal hindbrain (often called cardiac and posterior vagal neural crest) migrate long distances to form cell types as diverse as heart muscle and enteric ganglia, abnormalities of which lead to common congenital birth defects. Here, we explore whether individual caudal hindbrain neural crest precursors are multipotent or predetermined toward these particular fates and destinations. To this end, we perform lineage tracing of chick neural crest cells at single-cell resolution using two complementary approaches: retrovirally mediated multiplex clonal analysis and single-cell photoconversion. Both methods show that the majority of these neural crest precursors are multipotent with many clones producing mesenchymal as well as neuronal derivatives. Time-lapse imaging demonstrates that sister cells can migrate in distinct directions, suggesting stochasticity in choice of migration path. Perturbation experiments further identify guidance cues acting on cells in the pharyngeal junction that can influence this choice; loss ofCXCR4signaling results in failure to migrate to the heart but no influence on migration toward the foregut, whereas loss ofRETsignaling does the opposite. Taken together, the results suggest that environmental influences rather than intrinsic information govern cell fate choice of multipotent caudal hindbrain neural crest cells.

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