scholarly journals Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation

2018 ◽  
Vol 115 (12) ◽  
pp. E2888-E2897 ◽  
Author(s):  
Simon Mitchell ◽  
Koushik Roy ◽  
Thomas A. Zangle ◽  
Alexander Hoffmann
Keyword(s):  
Population Dynamics ◽  
B Cell ◽  
Cell Fate ◽  
Cell Population ◽  
B Lymphocyte ◽  
Population Expansion ◽  
Hematopoietic Stem ◽  
Cell Population Dynamics ◽  
Cell Fate Decisions ◽  
Founder Cells

Rapid antibody production in response to invading pathogens requires the dramatic expansion of pathogen-derived antigen-specific B lymphocyte populations. Whether B cell population dynamics are based on stochastic competition between competing cell fates, as in the development of competence by the bacterium Bacillus subtilis, or on deterministic cell fate decisions that execute a predictable program, as during the development of the worm Caenorhabditis elegans, remains unclear. Here, we developed long-term live-cell microscopy of B cell population expansion and multiscale mechanistic computational modeling to characterize the role of molecular noise in determining phenotype heterogeneity. We show that the cell lineage trees underlying B cell population dynamics are mediated by a largely predictable decision-making process where the heterogeneity of cell proliferation and death decisions at any given timepoint largely derives from nongenetic heterogeneity in the founder cells. This means that contrary to previous models, only a minority of genetically identical founder cells contribute the majority to the population response. We computationally predict and experimentally confirm nongenetic molecular determinants that are predictive of founder cells’ proliferative capacity. While founder cell heterogeneity may arise from different exposure histories, we show that it may also be due to the gradual accumulation of small amounts of intrinsic noise during the lineage differentiation process of hematopoietic stem cells to mature B cells. Our finding of the largely deterministic nature of B lymphocyte responses may provide opportunities for diagnostic and therapeutic development.

scholarly journals Notch Signaling in B Cell Immune Responses

2021 ◽  
Vol 11 ◽  
Author(s):  
Matthew Garis ◽  
Lee Ann Garrett-Sinha
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
B Lymphocyte ◽  
Notch Signaling Pathway ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance

The Notch signaling pathway is highly evolutionarily conserved, dictating cell fate decisions and influencing the survival and growth of progenitor cells that give rise to the cells of the immune system. The roles of Notch signaling in hematopoietic stem cell maintenance and in specification of T lineage cells have been well-described. Notch signaling also plays important roles in B cells. In particular, it is required for specification of marginal zone type B cells, but Notch signaling is also important in other stages of B cell development and activation. This review will focus on established and new roles of Notch signaling during B lymphocyte lineage commitment and describe the function of Notch within mature B cells involved in immune responses.

scholarly journals Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells

2005 ◽  
Vol 201 (9) ◽  
pp. 1361-1366 ◽  
Author(s):  
Mari H. Dallas ◽  
Barbara Varnum-Finney ◽  
Colleen Delaney ◽  
Keizo Kato ◽  
Irwin D. Bernstein
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Fate ◽  
Precursor Cells ◽  
Hematopoietic Stem ◽  
Notch Ligand ◽  
Murine Bone Marrow ◽  
Cell Fate Decisions ◽  
Multiple Cell ◽  
B Cell Precursors

Notch signaling regulates multiple cell fate decisions by hematopoietic precursors. To address whether different amounts of Notch ligand influence lineage choices, we cultured murine bone marrow lin−Sca-1+c-kit+ cells with increasing densities of immobilized Delta1ext-IgG consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1. We found that relatively lower densities of Delta1ext-IgG enhanced the generation of Sca-1+c-kit+ cells, Thy1+CD25+ early T cell precursors, and B220+CD43−/lo cells that, when cocultured with OP9 stroma cells, differentiated into CD19+ early B cell precursors. Higher densities of Delta1ext-IgG also enhanced the generation of Sca-1+c-kit+ precursor cells and promoted the development of Thy1+CD25+ cells, but inhibited the development of B220+CD43−/lo cells. Analyses of further isolated precursor populations suggested that the enhanced generation of T and B cell precursors resulted from the effects on multipotent rather than lymphoid-committed precursors. The results demonstrate the density-dependent effects of Delta1 on fate decisions of hematopoietic precursors at multiple maturational stages and substantiate the previously unrecognized ability of Delta1 to enhance the development of both early B and T precursor cells.

Mastermind critically regulates Notch-mediated lymphoid cell fate decisions

Blood ◽  
2004 ◽  
Vol 104 (6) ◽  
pp. 1696-1702 ◽  
Author(s):  
Ivan Maillard ◽  
Andrew P. Weng ◽  
Andrea C. Carpenter ◽  
Carlos G. Rodriguez ◽  
Hong Sai ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Fate ◽  
Critical Role ◽  
Family Members ◽  
Notch Pathway ◽  
Dominant Negative ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions

Abstract During lymphoid development, Notch1 plays a critical role in the T-cell/B-cell lineage decision, while Notch2 is essential for marginal zone B-cell (MZB) development. Notch pathway activation induces translocation of intracellular Notch (ICN) to the nucleus, where it interacts with the transcription factor CSL (CBF1/RBP-Jk, Suppressor of Hairless, Lag-1). In vitro, ICN binds Mastermind-like proteins, which act as potent Notch coactivators. Three MAML family members (MAML1-3) have been identified in mammals, but their importance in vivo is unknown. To investigate the function of MAMLs in hematopoietic development, we introduced a dominant negative (DN) mutant of MAML1, capable of inhibiting Notch1-4, in murine hematopoietic stem cells. DNMAML1 resulted in early inhibition of T-cell development and the appearance of intrathymic B cells, phenotypes consistent with Notch1 inhibition. The T-cell differentiation block was as profound as that produced by enforced expression of the Notch modulator Deltex1. In DNMAML1-transduced spleen cells, a dramatic decrease in MZB cells was present, consistent with Notch2 inhibition. In contrast, Deltex1 did not decrease MZB cell numbers. These results suggest a critical role for MAMLs during Notch-mediated cell fate decisions in vivo and indicate that DNMAML1, but not Deltex1, can be used to interfere with the function of multiple Notch family members. (Blood. 2004;104:1696-1702)

scholarly journals UPMaBoSS: a novel framework for dynamic cell population modeling

2020 ◽  
Author(s):  
Gautier Stoll ◽  
Aurélien Naldi ◽  
Vincent Noël ◽  
Eric Viara ◽  
Emmanuel Barillot ◽  
...  
Keyword(s):  
Population Dynamics ◽  
Cell Fate ◽  
Cellular Networks ◽  
Cell Population ◽  
Cell Fate Decisions ◽  
Dynamic Cell ◽  
Drug Treatments ◽  
A Cell ◽  
The Impact

AbstractOne of the aims of mathematical modeling is to understand and simulate the effects of biological perturbations and suggest ways to intervene and reestablish proper cell functioning. However, it remains a challenge, especially when considering the dynamics at the level of a cell population, with cells dying, dividing and interacting. Here, we introduce a novel framework for the dynamical modelling of cell populations packaged into a dedicated tool, UPMaBoSS. We rely on the preexisting tool MaBoSS, which enables probabilistic simulations of cellular networks, and add a novel layer to account for cell interactions and population dynamics. We illustrate our methodology by means of a case study dealing with TNF-induced cell death. Interestingly, the simulation of cell population dynamics with UPMaBoSS reveals a mechanism of resistance triggered by TNF treatment. This appoach can be applied to diverse models of cellular networks, for example to study the impact of ligand release or drug treatments on cell fate decisions, such as commitment to proliferation, differentiation, apoptosis, etc. Relatively easy to encode, UPMaBoSS simulations require only moderate computational power and execution time.To ease the reproduction of simulations, we provide several Jupyter notebooks that can be accessed within a new release of the CoLoMoTo Docker image, which contains all required software and the example models.

Flow-cytometric cell counting and DNA estimation for the study of plant cell population dynamics

1994 ◽  
Vol 39 (3) ◽  
pp. 251-259 ◽  
Author(s):  
Fernando T. Nicoloso ◽  
John Val ◽  
Maarten van der Keur ◽  
Frank van Iren ◽  
Jan W. Kijne
Keyword(s):  
Population Dynamics ◽  
Cell Population ◽  
Plant Cell ◽  
Cell Counting ◽  
Cell Population Dynamics ◽  
Flow Cytometric ◽  
Flow Cytometric Cell

scholarly journals Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q− polycythemia vera

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2812-2821 ◽  
Author(s):  
Fabiana Perna ◽  
Nadia Gurvich ◽  
Ruben Hoya-Arias ◽  
Omar Abdel-Wahab ◽  
Ross L. Levine ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Myeloproliferative Neoplasms ◽  
Erythroid Differentiation ◽  
Polycomb Group ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
Cd34 Cells

Abstract L3MBTL1, the human homolog of the Drosophila L(3)MBT polycomb group tumor suppressor gene, is located on chromosome 20q12, within the common deleted region identified in patients with 20q deletion-associated polycythemia vera, myelodysplastic syndrome, and acute myeloid leukemia. L3MBTL1 is expressed within hematopoietic CD34+ cells; thus, it may contribute to the pathogenesis of these disorders. To define its role in hematopoiesis, we knocked down L3MBTL1 expression in primary hematopoietic stem/progenitor (ie, CD34+) cells isolated from human cord blood (using short hairpin RNAs) and observed an enhanced commitment to and acceleration of erythroid differentiation. Consistent with this effect, overexpression of L3MBTL1 in primary hematopoietic CD34+ cells as well as in 20q− cell lines restricted erythroid differentiation. Furthermore, L3MBTL1 levels decrease during hemin-induced erythroid differentiation or erythropoietin exposure, suggesting a specific role for L3MBTL1 down-regulation in enforcing cell fate decisions toward the erythroid lineage. Indeed, L3MBTL1 knockdown enhanced the sensitivity of hematopoietic stem/progenitor cells to erythropoietin (Epo), with increased Epo-induced phosphorylation of STAT5, AKT, and MAPK as well as detectable phosphorylation in the absence of Epo. Our data suggest that haploinsufficiency of L3MBTL1 contributes to some (20q−) myeloproliferative neoplasms, especially polycythemia vera, by promoting erythroid differentiation.

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

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4342-4346 ◽  
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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