Cell circuits and niches controlling B cell development

Zehentmeier, Sandra; Pereira, João P.

doi:10.1111/imr.12749

Cited by 62 publications

(66 citation statements)

References 186 publications

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“…In addition, lymphoid-bi-HSCs or B-cell progenitors might be primarily localized to osteoblastic niches. Osteoblastic MSCs, together with perivascular BM MSCs, support B-lymphopoiesis by producing lymphocyte-specific cytokines such as Cxcl12 and IL-7 [ 209 – 213 ]. Furthermore, T-reg cells in endosteal niches provide an immune-privileged microenvironment to protect HSCs from immune attack [ 214 – 216 ].…”

Section: Age-related Hsc Niche Changesmentioning

confidence: 99%

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

et al. 2020

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Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated.

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Section: Age-related Hsc Niche Changesmentioning

confidence: 99%

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

et al. 2020

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“…This has implications for future treatment of ICF patients, since, for example, genome editing of stem cells becomes a potential therapeutic strategy in the treatment of ICF4 patients ( 45 ). Many factors regulate hematopoiesis, including IL-7 which impairs B cell development ( 46 , 47 ). However, a defect in IL-7 production cannot account for our findings, since IL-7 is predominantly produced by cells which are not of hematopoietic origin ( 46 , 47 ), and our results demonstrate a hematopoietic cell-intrinsic defect.…”

Section: Discussionmentioning

confidence: 99%

“…Many factors regulate hematopoiesis, including IL-7 which impairs B cell development ( 46 , 47 ). However, a defect in IL-7 production cannot account for our findings, since IL-7 is predominantly produced by cells which are not of hematopoietic origin ( 46 , 47 ), and our results demonstrate a hematopoietic cell-intrinsic defect. While we do not have proof that Lsh has a B cell intrinsic effect, it is a possibility, and reduced IL-7 receptor alpha expression or impaired Stat5 activation may contribute to the phenotype ( 46 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Ren

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Mutation of HELLS (Helicase, Lymphoid-Specific)/Lsh in human DNA causes a severe immunodeficiency syndrome, but the nature of the defect remains unknown. We assessed here the role of Lsh in hematopoiesis using conditional Lsh knockout mice with expression of Mx1 or Vav Cre-recombinase. Bone marrow transplantation studies revealed that Lsh depletion in hematopoietic stem cells severely reduced B cell numbers and impaired B cell development in a hematopoietic cell-autonomous manner. Lsh-deficient mice without bone marrow transplantation exhibited lower Ig levels in vivo compared to controls despite normal peripheral B cell numbers. Purified B lymphocytes proliferated normally but produced less immunoglobulins in response to in vitro stimulation, indicating a reduced capacity to undergo class switch recombination (CSR). Analysis of germline transcripts, examination of double-stranded breaks using biotin-labeling DNA break assay, and End-seq analysis indicated that the initiation of the recombination process was unscathed. In contrast, digestion–circularization PCR analysis and high-throughput sequencing analyses of CSR junctions and a chromosomal break repair assay indicated an impaired ability of the canonical end-joining pathway in Lsh-deficient B cells. Our data suggest a hematopoietic cell-intrinsic role of Lsh in B cell development and in CSR providing a potential target for immunodeficiency therapy.

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“…Tokoyoda and colleagues have proposed the participation of spatially excluding niches of CXCL12 and IL7 producing stromal cells in the cell expansion/arrest periods of lymphoid precursors to allow the proper V(D)J recombination and further assembly of pre-BCR and BCR, concomitant to a dynamic cell transit from one to another ( Tokoyoda et al, 2004 ; Park et al, 2013 ; Clark et al, 2013 ). Though, recent data suggests that IL-7-secreting MSCs are also the highest producers of CXCL12, and that the IL-7/CXCL12 signaling shift depends on IL-7 availability and on the regulation of CXCR4 ( Cordeiro Gomes et al, 2016 ; Fistonich et al, 2018 ; Zehentmeier & Pereira, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…During systemic inflammation, the plasticity of primitive cells leads hematopoiesis to undergo adjustments upon proliferation and cell fate reprogramming in response to stress mediated by proinflammatory factors and recognition of damage- and pathogen-associated molecular patterns via toll-like receptors (TLRs) ( Welner, Pelayo & Kincade, 2008 ; Enciso et al, 2016 ; Balandrán et al, 2017 ). The implication of these phenomena in the hematopoietic niches and their supported developing cells on disease progression is research in progress ( Terashima et al, 2016 ; Zehentmeier & Pereira, 2019 ; Enciso et al, 2016 ; Lévesque et al, 2003 ). In addition to ALL, increasing evidence on acute and chronic diseases have shown unfunctional B-lymphopoiesis linked to extrinsic pro-inflammatory pathways leading to intracellular changes in lymphoid progenitors.…”

Section: Introductionmentioning

confidence: 99%

Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies

Enciso

Mendoza

Álvarez-Buylla

et al. 2020

PeerJ

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Background The blockage at the early B lymphoid cell development pathway within the bone marrow is tightly associated with hematopoietic and immune diseases, where the disruption of basal regulatory networks prevents the continuous replenishment of functional B cells. Dynamic computational models may be instrumental for the comprehensive understanding of mechanisms underlying complex differentiation processes and provide novel prediction/intervention platforms to reinvigorate the system. Methods By reconstructing a three-module regulatory network including genetic transcription, intracellular transduction, and microenvironment communication, we have investigated the early B lineage cell fate decisions in normal and pathological settings. The early B cell differentiation network was simulated as a Boolean model and then transformed, using fuzzy logic, to a continuous model. We tested null and overexpression mutants to analyze the emergent behavior of the network. Due to its importance in inflammation, we investigated the effect of NFkB induction at different early B cell differentiation stages. Results While the exhaustive synchronous and asynchronous simulation of the early B cell regulatory network (eBCRN) reproduced the configurations of the hematopoietic progenitors and early B lymphoid precursors of the pathway, its simulation as a continuous model with fuzzy logics suggested a transient IL-7R+ ProB-to-Pre-B subset expressing pre-BCR and a series of dominant B-cell transcriptional factors. This conspicuous differentiating cell population up-regulated CXCR7 and reduced CXCR4 and FoxO1 expression levels. Strikingly, constant but intermediate NFkB signaling at specific B cell differentiation stages allowed stabilization of an aberrant CXCR7+ pre-B like phenotype with apparent affinity to proliferative signals, while under constitutive overactivation of NFkB, such cell phenotype was aberrantly exacerbated from the earliest stage of common lymphoid progenitors. Our mutant models revealed an abnormal delay in the BCR assembly upon NFkB activation, concomitant to sustained Flt3 signaling, down-regulation of Ebf1, Irf4 and Pax5 genes transcription, and reduced Ig recombination, pointing to a potential lineage commitment blockage. Discussion For the first time, an inducible CXCR7hi B cell precursor endowed with the potential capability of shifting central lymphoid niches, is inferred by computational modeling. Its phenotype is compatible with that of leukemia-initiating cells and might be the foundation that bridges inflammation with blockage-related malignancies and a wide range of immunological diseases. Besides the predicted differentiation impairment, inflammation-inducible phenotypes open the possibility of newly formed niches colonized by the reported precursor. Thus, emergent bone marrow ecosystems are predicted following a pro-inflammatory induction, that may lead to hematopoietic instability associated to blockage pathologies.

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Cell circuits and niches controlling B cell development

Cited by 62 publications

References 186 publications

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches

Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

Dynamical modeling predicts an inflammation-inducible CXCR7+ B cell precursor with potential implications in lymphoid blockage pathologies

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