Differential Effects of Notch Ligands Delta-1 and Jagged-1 in Human Lymphoid Differentiation

Notch signaling is known to differentially affect the development of lymphoid B and T cell lineages, but it remains unclear whether such effects are specifically dependent on distinct Notch ligands. Using a cell coculture assay we observed that the Notch ligand Delta-1 completely inhibits the differentiation of human hematopoietic progenitors into the B cell lineage while promoting the emergence of cells with a phenotype of T cell/natural killer (NK) precursors. In contrast, Jagged-1 did not disturb either B or T cell/NK development. Furthermore, cells cultured in the presence of either Delta-1 or Jagged-1 can acquire a phenotype of NK cells, and Delta-1, but not Jagged-1, permits the emergence of a de novo cell population coexpressing CD4 and CD8. Our results thus indicate that distinct Notch ligands can mediate differential effects of Notch signaling and provide a useful system to further address cell-fate decision processes in lymphopoiesis.

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Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor–Ligand Interactions

Journal of Experimental Medicine ◽

10.1084/jem.20040394 ◽

2004 ◽

Vol 200 (4) ◽

pp. 469-479 ◽

Cited By ~ 236

Author(s):

Thomas M. Schmitt ◽

Maria Ciofani ◽

Howard T. Petrie ◽

Juan Carlos Zúñiga-Pflücker

Keyword(s):

T Cell ◽

Notch Signaling ◽

Cell Fate ◽

Stromal Cells ◽

Cell Lineage ◽

Notch Receptor ◽

Lineage Specification ◽

Cell Specification ◽

Receptor Ligand ◽

Ligand Interactions

Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. Thus, additional requirements for Notch signals and the timing of these events relative to intrathymic differentiation remain unknown. Here, we address this issue by culturing subsets of CD4 CD8 double negative (DN) thymocytes on control stromal cells or stromal cells expressing Delta-like 1 (Dll1). All DN subsets were found to require Notch signals to differentiate into CD4+ CD8+ T cells. Using clonal analyses, we show that CD44+ CD25+ (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44+ CD25− (DN1) thymocytes when Notch signaling was absent. These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor–ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage.

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Dll4–Notch signaling in Flt3-independent dendritic cell development and autoimmunity in mice

Journal of Experimental Medicine ◽

10.1084/jem.20111615 ◽

2012 ◽

Vol 209 (5) ◽

pp. 1011-1028 ◽

Cited By ~ 34

Author(s):

Fabienne Billiard ◽

Camille Lobry ◽

Guillaume Darrasse-Jèze ◽

Janelle Waite ◽

Xia Liu ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

Notch Signaling ◽

Cell Fate ◽

Treg Cell ◽

De Novo ◽

Alternative Pathway ◽

Treg Cells ◽

Cell Development

Delta-like ligand 4 (Dll4)–Notch signaling is essential for T cell development and alternative thymic lineage decisions. How Dll4–Notch signaling affects pro-T cell fate and thymic dendritic cell (tDC) development is unknown. We found that Dll4 pharmacological blockade induces accumulation of tDCs and CD4+CD25+FoxP3+ regulatory T cells (Treg cells) in the thymic cortex. Both genetic inactivation models and anti-Dll4 antibody (Ab) treatment promote de novo natural Treg cell expansion by a DC-dependent mechanism that requires major histocompatibility complex II expression on DCs. Anti-Dll4 treatment converts CD4−CD8−c-kit+CD44+CD25− (DN1) T cell progenitors to immature DCs that induce ex vivo differentiation of naive CD4+ T cells into Treg cells. Induction of these tolerogenic DN1-derived tDCs and the ensuing expansion of Treg cells are Fms-like tyrosine kinase 3 (Flt3) independent, occur in the context of transcriptional up-regulation of PU.1, Irf-4, Irf-8, and CSF-1, genes critical for DC differentiation, and are abrogated in thymectomized mice. Anti-Dll4 treatment fully prevents type 1 diabetes (T1D) via a Treg cell–mediated mechanism and inhibits CD8+ T cell pancreatic islet infiltration. Furthermore, a single injection of anti-Dll4 Ab reverses established T1D. Disease remission and recurrence are correlated with increased Treg cell numbers in the pancreas-draining lymph nodes. These results identify Dll4–Notch as a novel Flt3-alternative pathway important for regulating tDC-mediated Treg cell homeostasis and autoimmunity.

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Morphogenesis of the C. elegans hermaphrodite uterus

Development ◽

10.1242/dev.122.11.3617 ◽

1996 ◽

Vol 122 (11) ◽

pp. 3617-3626 ◽

Cited By ~ 11

Author(s):

A.P. Newman ◽

J.G. White ◽

P.W. Sternberg

Keyword(s):

Cell Fate ◽

Cell Lineage ◽

Cell Types ◽

Cell Interaction ◽

Cell Fate Decision ◽

Cell Fates ◽

C Elegans ◽

A Cell ◽

Anchor Cell ◽

Fate Decision

We have undertaken electron micrographic reconstruction of the Caenorhabditis elegans hermaphrodite uterus and determined the correspondence between cells defined by their lineage history and differentiated cell types. In this organ, many cells do not move during morphogenesis and the cell lineage may function to put cells where they are needed. Differentiated uterine cell types include the toroidal ut cells that make structural epithelium, and specialized utse and uv cells that make the connection between the uterus and the vulva. A cell fate decision in which the anchor cell (AC) induces adjacent ventral uterine intermediate precursor cells to adopt the pi fate, rather than the ground state rho, has profound consequences for terminal differentiation: all pi progeny are directly involved in making the uterine-vulval connection whereas all rho progeny contribute to ut toroids or the uterine-spermathecal valve. In addition to specifying certain uterine cell fates, the AC also induces the vulva. Its multiple inductions thereby function to coordinate the connection of an internal to an external epithelium. The AC induces the pi cells and ultimately fuses with a subset of their progeny. This is an example of reciprocal cell-cell interaction that can be studied at single cell resolution. The AC is thus a transitory cell type that plays a pivotal role in organizing the morphogenesis of the uterine-vulval connection.

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Faculty Opinions recommendation of A positive-feedback-based bistable 'memory module' that governs a cell fate decision.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014093.206673 ◽

2004 ◽

Author(s):

Hiten Madhani

Keyword(s):

Cell Fate ◽

Positive Feedback ◽

Cell Fate Decision ◽

Memory Module ◽

A Cell ◽

Fate Decision

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Aspects of the biology of regeneration and repair in the human gastrointestinal tract

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1998.0257 ◽

1998 ◽

Vol 353 (1370) ◽

pp. 925-933 ◽

Cited By ~ 45

Author(s):

Nicholas A. Wright

Keyword(s):

Stem Cells ◽

Gastric Gland ◽

Cell Lineage ◽

Mucosal Ulceration ◽

Cell Lineages ◽

Trefoil Peptides ◽

Pyloric Mucosa ◽

A Cell ◽

Epidermal Growth ◽

Altered Gene

The main pathways of epithelial differentiation in the intestine, Paneth, mucous, endocrine and columnar cell lineages are well recognized. However, in abnormal circumstances, for example in mucosal ulceration, a cell lineage with features distinct from these emerges, which has often been dismissed in the past as ‘pyloric’ metaplasia, because of its morphological resemblance to the pyloric mucosa in the stomach. However, we can conclude that this cell lineage has a defined phenotype unique in gastrointestinal epithelia, has a histogenesis that resembles that of Brunner's glands, but acquires a proliferative organization similar to that of the gastric gland. It expresses several peptides of particular interest, including epidermal growth factor, the trefoil peptides TFF1, TFF2, TFF3, lysozyme and PSTI. The presence of this lineage also appears to cause altered gene expression in adjacent indigenous cell lineages. We propose that this cell lineage is induced in gastrointestinal stem cells as a result of chronic mucosal ulceration, and plays an important part in ulcer healing; it should therefore be added to the repertoire of gastrointestinal stem cells.

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Cell fate clusters in ICM organoids arise from cell fate heredity and division: a modelling approach

Scientific Reports ◽

10.1038/s41598-020-80141-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Tim Liebisch ◽

Armin Drusko ◽

Biena Mathew ◽

Ernst H. K. Stelzer ◽

Sabine C. Fischer ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Division ◽

Cell Fate ◽

Inner Cell Mass ◽

Cell Mass ◽

Cell Lineage ◽

Cell Fate Decision ◽

Cell Fate Decisions ◽

Chemical Signalling ◽

Fate Decision

AbstractDuring the mammalian preimplantation phase, cells undergo two subsequent cell fate decisions. During the first decision, the trophectoderm and the inner cell mass are formed. Subsequently, the inner cell mass segregates into the epiblast and the primitive endoderm. Inner cell mass organoids represent an experimental model system, mimicking the second cell fate decision. It has been shown that cells of the same fate tend to cluster stronger than expected for random cell fate decisions. Three major processes are hypothesised to contribute to the cell fate arrangements: (1) chemical signalling; (2) cell sorting; and (3) cell proliferation. In order to quantify the influence of cell proliferation on the observed cell lineage type clustering, we developed an agent-based model accounting for mechanical cell–cell interaction, i.e. adhesion and repulsion, cell division, stochastic cell fate decision and cell fate heredity. The model supports the hypothesis that initial cell fate acquisition is a stochastically driven process, taking place in the early development of inner cell mass organoids. Further, we show that the observed neighbourhood structures can emerge solely due to cell fate heredity during cell division.

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ming is expressed in neuroblast sublineages and regulates gene expression in the Drosophila central nervous system

Development ◽

10.1242/dev.116.4.943 ◽

1992 ◽

Vol 116 (4) ◽

pp. 943-952 ◽

Cited By ~ 8

Author(s):

X. Cui ◽

C.Q. Doe

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

Cell Fate ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Cell Lineage ◽

Cell Lineages ◽

Finger Protein ◽

Cell Diversity

Cell diversity in the Drosophila central nervous system (CNS) is primarily generated by the invariant lineage of neural precursors called neuroblasts. We used an enhancer trap screen to identify the ming gene, which is transiently expressed in a subset of neuroblasts at reproducible points in their cell lineage (i.e. in neuroblast ‘sublineages’), suggesting that neuroblast identity can be altered during its cell lineage. ming encodes a predicted zinc finger protein and loss of ming function results in precise alterations in CNS gene expression, defects in axonogenesis and embryonic lethality. We propose that ming controls cell fate within neuroblast cell lineages.

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Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development

Blood ◽

10.1182/blood-2002-10-3139 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4342-4346 ◽

Cited By ~ 42

Author(s):

Claudiu V. Cotta ◽

Zheng Zhang ◽

Hyung-Gyoon Kim ◽

Christopher A. Klug

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Fate ◽

Nk Cell ◽

Cell Lineage ◽

Blood Analysis ◽

Hematopoietic Stem ◽

Peripheral Blood Analysis

Abstract Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.

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Early developmental asymmetries in cell lineage trees in living individuals

10.1101/2020.08.24.265751 ◽

2020 ◽

Author(s):

Liana Fasching ◽

Yeongjun Jang ◽

Simone Tomasi ◽

Jeremy Schreiner ◽

Livia Tomasini ◽

...

Keyword(s):

Cell Fate ◽

Cell Lineage ◽

Postmortem Brain ◽

Cell Lineages ◽

Human Specimen ◽

Balanced Contributions ◽

Health And Disease ◽

Induced Pluripotent ◽

Lineage Trees ◽

Early Developmental

AbstractPost-zygotic mosaic mutations can be used to track cell lineages in humans. By using cell cloning and induced pluripotent cell lines, we analyzed early cell lineages in two living individuals (a patient and a control), and a postmortem human specimen. Of ten reconstructed post-zygotic divisions, none resulted in balanced contributions of daughter lineages to tissues. In both living individuals one of two lineages from the first cleavage was dominant across tissues, with 90% frequency in blood. We propose that the efficiency of DNA repair contributes to lineage imbalance. Allocation of lineages in postmortem brain correlated with anterior-posterior axis, associating lineage history with cell fate choices in embryos. Recurrence of germline variants as mosaic suggested that certain loci may be particularly susceptible to mutagenesis. We establish a minimally invasive framework for defining cell lineages in any living individual, which paves the way for studying their relevance in health and disease.

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