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Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity.
Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G
(2019) Dev Cell 48: 49-63.e7
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Endocrine Cells, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Mice, Nerve Tissue Proteins, Organogenesis, Pancreas, Transcription Factors
Show Abstract · Added February 6, 2019
In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet cell types: α, β, δ, and γ; when and how the Neurog3 cells choose cell fate is unknown. Using single-cell RNA-seq, trajectory analysis, and combinatorial lineage tracing, we showed here that the Neurog3 cells co-expressing Myt1 (i.e., Myt1Neurog3) were biased toward β cell fate, while those not simultaneously expressing Myt1 (Myt1Neurog3) favored α fate. Myt1 manipulation only marginally affected α versus β cell specification, suggesting Myt1 as a marker but not determinant for islet-cell-type specification. The Myt1Neurog3 cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α cell specification, while Dnmt1 overexpression or Arx enhancer hypermethylation favored β cell production. Moreover, the pancreatic progenitors contained distinct Arx enhancer methylation states without transcriptionally definable sub-populations, a phenotype independent of Neurog3 activity. These data suggest that Neurog3-independent methylation on fate-determining gene enhancers specifies distinct endocrine-cell programs.
Published by Elsevier Inc.
1 Communities
1 Members
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13 MeSH Terms
Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium.
McCauley KB, Alysandratos KD, Jacob A, Hawkins F, Caballero IS, Vedaie M, Yang W, Slovik KJ, Morley M, Carraro G, Kook S, Guttentag SH, Stripp BR, Morrisey EE, Kotton DN
(2018) Stem Cell Reports 10: 1579-1595
MeSH Terms: Animals, Cell Differentiation, Cell Line, Cell Lineage, Cell Plasticity, Epithelium, Gene Expression Profiling, Genes, Reporter, Humans, Induced Pluripotent Stem Cells, Kinetics, Lung, Mice, Secretoglobins, Sequence Analysis, RNA, Single-Cell Analysis, Solubility, Spheroids, Cellular, Time Factors, Transcriptome, Wnt Signaling Pathway
Show Abstract · Added April 1, 2019
Lung epithelial lineages have been difficult to maintain in pure form in vitro, and lineage-specific reporters have proven invaluable for monitoring their emergence from cultured pluripotent stem cells (PSCs). However, reporter constructs for tracking proximal airway lineages generated from PSCs have not been previously available, limiting the characterization of these cells. Here, we engineer mouse and human PSC lines carrying airway secretory lineage reporters that facilitate the tracking, purification, and profiling of this lung subtype. Through bulk and single-cell-based global transcriptomic profiling, we find PSC-derived airway secretory cells are susceptible to phenotypic plasticity exemplified by the tendency to co-express both a proximal airway secretory program as well as an alveolar type 2 cell program, which can be minimized by inhibiting endogenous Wnt signaling. Our results provide global profiles of engineered lung cell fates, a guide for improving their directed differentiation, and a human model of the developing airway.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Wnt6 maintains anterior escort cells as an integral component of the germline stem cell niche.
Wang X, Page-McCaw A
(2018) Development 145:
MeSH Terms: Animals, Animals, Genetically Modified, Bone Morphogenetic Proteins, Cadherins, Cell Count, Cell Differentiation, Cell Lineage, Cell Survival, Drosophila Proteins, Drosophila melanogaster, Female, Germ Cells, Ligands, Models, Biological, Ovary, Signal Transduction, Stem Cell Niche, Wnt Proteins
Show Abstract · Added March 20, 2018
Stem cells reside in a niche, a local environment whose cellular and molecular complexity is still being elucidated. In ovaries, germline stem cells depend on cap cells for self-renewing signals and physical attachment. Germline stem cells also contact the anterior escort cells, and here we report that anterior escort cells are absolutely required for germline stem cell maintenance. When escort cells die from impaired Wnt signaling or expression, the loss of anterior escort cells causes loss of germline stem cells. Anterior escort cells function as an integral niche component by promoting DE-cadherin anchorage and by transiently expressing the Dpp ligand to promote full-strength BMP signaling in germline stem cells. Anterior escort cells are maintained by Wnt6 ligands produced by cap cells; without Wnt6 signaling, anterior escort cells die leaving vacancies in the niche, leading to loss of germline stem cells. Our data identify anterior escort cells as constituents of the germline stem cell niche, maintained by a cap cell-produced Wnt6 survival signal.
© 2018. Published by The Company of Biologists Ltd.
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18 MeSH Terms
Differential Expression of NF2 in Neuroepithelial Compartments Is Necessary for Mammalian Eye Development.
Moon KH, Kim HT, Lee D, Rao MB, Levine EM, Lim DS, Kim JW
(2018) Dev Cell 44: 13-28.e3
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Lineage, Cell Polarity, Cells, Cultured, Cilia, Gene Expression Regulation, Developmental, Humans, Hyperplasia, Mice, Mice, Knockout, Neural Stem Cells, Neurofibromin 2, Organogenesis, Phenotype, Phosphoproteins, Protein-Serine-Threonine Kinases, Retinal Pigment Epithelium, Transcription Factors
Show Abstract · Added February 14, 2018
The optic neuroepithelial continuum of vertebrate eye develops into three differentially growing compartments: the retina, the ciliary margin (CM), and the retinal pigment epithelium (RPE). Neurofibromin 2 (Nf2) is strongly expressed in slowly expanding RPE and CM compartments, and the loss of mouse Nf2 causes hyperplasia in these compartments, replicating the ocular abnormalities seen in human NF2 patients. The hyperplastic ocular phenotypes were largely suppressed by heterozygous deletion of Yap and Taz, key targets of the Nf2-Hippo signaling pathway. We also found that, in addition to feedback transcriptional regulation of Nf2 by Yap/Taz in the CM, activation of Nf2 expression by Mitf in the RPE and suppression by Sox2 in retinal progenitor cells are necessary for the differential growth of the corresponding cell populations. Together, our findings reveal that Nf2 is a key player that orchestrates the differential growth of optic neuroepithelial compartments during vertebrate eye development.
Copyright © 2017 Elsevier Inc. All rights reserved.
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1 Members
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19 MeSH Terms
Unsupervised Trajectory Analysis of Single-Cell RNA-Seq and Imaging Data Reveals Alternative Tuft Cell Origins in the Gut.
Herring CA, Banerjee A, McKinley ET, Simmons AJ, Ping J, Roland JT, Franklin JL, Liu Q, Gerdes MJ, Coffey RJ, Lau KS
(2018) Cell Syst 6: 37-51.e9
MeSH Terms: Algorithms, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Humans, Image Cytometry, Intestinal Mucosa, Intestine, Small, K562 Cells, Mice, Mice, Inbred C57BL, RNA, Sequence Analysis, RNA, Single-Cell Analysis
Show Abstract · Added April 3, 2018
Modern single-cell technologies allow multiplexed sampling of cellular states within a tissue. However, computational tools that can infer developmental cell-state transitions reproducibly from such single-cell data are lacking. Here, we introduce p-Creode, an unsupervised algorithm that produces multi-branching graphs from single-cell data, compares graphs with differing topologies, and infers a statistically robust hierarchy of cell-state transitions that define developmental trajectories. We have applied p-Creode to mass cytometry, multiplex immunofluorescence, and single-cell RNA-seq data. As a test case, we validate cell-state-transition trajectories predicted by p-Creode for intestinal tuft cells, a rare, chemosensory cell type. We clarify that tuft cells are specified outside of the Atoh1-dependent secretory lineage in the small intestine. However, p-Creode also predicts, and we confirm, that tuft cells arise from an alternative, Atoh1-driven developmental program in the colon. These studies introduce p-Creode as a reliable method for analyzing large datasets that depict branching transition trajectories.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
1 Communities
2 Members
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15 MeSH Terms
Stochastic priming and spatial cues orchestrate heterogeneous clonal contribution to mouse pancreas organogenesis.
Larsen HL, Martín-Coll L, Nielsen AV, Wright CVE, Trusina A, Kim YH, Grapin-Botton A
(2017) Nat Commun 8: 605
MeSH Terms: Acinar Cells, Animals, Cell Differentiation, Cell Lineage, Cell Proliferation, Computer Simulation, Gene Expression Profiling, Mice, Organogenesis, Pancreas, Single-Cell Analysis
Show Abstract · Added October 3, 2017
Spatiotemporal balancing of cellular proliferation and differentiation is crucial for postnatal tissue homoeostasis and organogenesis. During embryonic development, pancreatic progenitors simultaneously proliferate and differentiate into the endocrine, ductal and acinar lineages. Using in vivo clonal analysis in the founder population of the pancreas here we reveal highly heterogeneous contribution of single progenitors to organ formation. While some progenitors are bona fide multipotent and contribute progeny to all major pancreatic cell lineages, we also identify numerous unipotent endocrine and ducto-endocrine bipotent clones. Single-cell transcriptional profiling at E9.5 reveals that endocrine-committed cells are molecularly distinct, whereas multipotent and bipotent progenitors do not exhibit different expression profiles. Clone size and composition support a probabilistic model of cell fate allocation and in silico simulations predict a transient wave of acinar differentiation around E11.5, while endocrine differentiation is proportionally decreased. Increased proliferative capacity of outer progenitors is further proposed to impact clonal expansion.
2 Communities
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11 MeSH Terms
Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach.
Choi E, Lantz TL, Vlacich G, Keeley TM, Samuelson LC, Coffey RJ, Goldenring JR, Powell AE
(2018) Gut 67: 1595-1605
MeSH Terms: Animals, Biomarkers, Cell Lineage, Disease Models, Animal, Gastric Mucosa, Membrane Glycoproteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Predictive Value of Tests, Sensitivity and Specificity, Stem Cells, Stomach Ulcer, Wound Healing
Show Abstract · Added September 27, 2017
OBJECTIVE - Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice.
DESIGN - We performed lineage labelling using (Lrig1/YFP) or (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP-marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1- (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury.
RESULTS - Lrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy.
CONCLUSIONS - Lrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
1 Communities
3 Members
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14 MeSH Terms
Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.
Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA
(2017) Diabetes 66: 2175-2187
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Calcium Signaling, Cell Adhesion, Cell Cycle Proteins, Cell Lineage, Cell Polarity, Gene Expression, Gene Expression Regulation, Insulin-Secreting Cells, KATP Channels, Mice, Pancreatic Polypeptide-Secreting Cells, S100 Calcium Binding Protein A6, S100 Calcium-Binding Protein A4, S100 Proteins, Sulfonylurea Receptors
Show Abstract · Added June 2, 2017
We used mice lacking , a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Ca concentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking into pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purified β-cells confirmed an increase in gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca signaling, the maintenance of β-cell identity, and cell adhesion. The expression of and , two highly upregulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca] Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, , was confirmed to be directly controlled by Ca influx in β-cells. Interestingly, among the upregulated genes is , a putative marker of β-cell dedifferentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically elevated β-cell [Ca] in islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
© 2017 by the American Diabetes Association.
4 Communities
4 Members
0 Resources
18 MeSH Terms
Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction.
Gaskill CF, Carrier EJ, Kropski JA, Bloodworth NC, Menon S, Foronjy RF, Taketo MM, Hong CC, Austin ED, West JD, Means AL, Loyd JE, Merryman WD, Hemnes AR, De Langhe S, Blackwell TS, Klemm DJ, Majka SM
(2017) J Clin Invest 127: 2262-2276
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Bone Morphogenetic Protein Receptors, Type II, Cell Differentiation, Cell Lineage, Cells, Cultured, Humans, Lung, Mesenchymal Stem Cells, Mice, Transgenic, Microvessels, Neovascularization, Pathologic, Pericytes, Protein Stability, Pulmonary Fibrosis, Vasoconstriction, Wnt Signaling Pathway
Show Abstract · Added June 6, 2017
Pulmonary vascular disease is characterized by remodeling and loss of microvessels and is typically attributed to pathological responses in vascular endothelium or abnormal smooth muscle cell phenotypes. We have challenged this understanding by defining an adult pulmonary mesenchymal progenitor cell (MPC) that regulates both microvascular function and angiogenesis. The current understanding of adult MPCs and their roles in homeostasis versus disease has been limited by a lack of genetic markers with which to lineage label multipotent mesenchyme and trace the differentiation of these MPCs into vascular lineages. Here, we have shown that lineage-labeled lung MPCs expressing the ATP-binding cassette protein ABCG2 (ABCG2+) are pericyte progenitors that participate in microvascular homeostasis as well as adaptive angiogenesis. Activation of Wnt/β-catenin signaling, either autonomously or downstream of decreased BMP receptor signaling, enhanced ABCG2+ MPC proliferation but suppressed MPC differentiation into a functional pericyte lineage. Thus, enhanced Wnt/β-catenin signaling in ABCG2+ MPCs drives a phenotype of persistent microvascular dysfunction, abnormal angiogenesis, and subsequent exacerbation of bleomycin-induced fibrosis. ABCG2+ MPCs may, therefore, account in part for the aberrant microvessel function and remodeling that are associated with chronic lung diseases.
0 Communities
3 Members
0 Resources
17 MeSH Terms
The Vascular Wall: a Plastic Hub of Activity in Cardiovascular Homeostasis and Disease.
Awgulewitsch CP, Trinh LT, Hatzopoulos AK
(2017) Curr Cardiol Rep 19: 51
MeSH Terms: Blood Vessels, Cardiovascular Diseases, Cell Differentiation, Cell Lineage, Cell Plasticity, Epithelial-Mesenchymal Transition, Homeostasis, Humans, Stem Cells
Show Abstract · Added September 6, 2017
PURPOSE OF REVIEW - This review aims to summarize recent findings regarding the plasticity and fate switching among somatic and progenitor cells residing in the vascular wall of blood vessels in health and disease.
RECENT FINDINGS - Cell lineage tracing methods have identified multiple origins of stem cells, macrophages, and matrix-producing cells that become mobilized after acute or chronic injury of cardiovascular tissues. These studies also revealed that in the disease environment, resident somatic cells become plastic, thereby changing their stereotypical identities to adopt proinflammatory and profibrotic phenotypes. Currently, the functional significance of this heterogeneity among reparative cells is unknown. Furthermore, mechanisms that control cellular plasticity and fate decisions in the disease environment are poorly understood. Cardiovascular diseases are responsible for the majority of deaths worldwide. From a therapeutic perspective, these novel discoveries may identify new targets to improve the repair and regeneration of the cardiovascular system.
1 Communities
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9 MeSH Terms