The epigenetic influences of bone marrow and fetal liver stroma cells on the developmental potential of Ly-1pro-B lymphocyte clones

1989 ◽  
Vol 19 (2) ◽  
pp. 347-356 ◽  
Author(s):  
Ronald Palacios ◽  
Susanne Stuber ◽  
Anthonius Rolink
Keyword(s):  
Bone Marrow ◽  
B Lymphocyte ◽  
Fetal Liver ◽  
Developmental Potential

scholarly journals Monoclonal origin of B lymphocyte colony-forming cells in spleen colonies formed by multipotential hemopoietic stem cells

1978 ◽  
Vol 148 (6) ◽  
pp. 1468-1477 ◽  
Author(s):  
PK Lala ◽  
GR Johnson
Keyword(s):  
Bone Marrow ◽  
B Lymphocyte ◽  
Bone Marrow Cells ◽  
Fetal Liver ◽  
Absolute Number ◽  
Hemopoietic Stem Cell ◽  
Adult Bone Marrow ◽  
Clonal Origin ◽  
Adult Bone ◽  
Marrow Cells

Spleen colonies produced by transplanting lethally irradiated mice with either 12 day fetal liver or adult bone marrow cells were found to contain B- lymphocyte colony-forming cells (BL-CFC) . The proportion of BL-CFC positive spleen colonies did not increase substantially between 8 and 14 days after transplantation, the range being 18-45 percent. However, the absolute number of BL-CFC per spleen colony varied considerably (between 1 and 10,318), although the majority of colonies contained less than 200 BL-CFC. Irrespective of the time after transplantation, smaller spleen colonies were found to have a higher frequency of BL-CFC than larger spleen colonies. To determine the possible clonal origin of BL-CFC from spleen colony- forming unit (CFU-S), CBA mice were injected with equal numbers of CBA and CBA T(6)/T(6) fetal liver or adult bone marrow cells. Analysis of 7-15-day spleen colonies demonstrated that 90 percent were either exclusively T(6) positive or T(6) negative and approximately equal numbers ofboth colony types were observed. B-lymphocyte colonies were grown and successfully karyotyped from 19 spleen colonies. When compared with the original spleen colony karyotype the B-lymphocyte colony cells karyotype was identical in all 19 cases. In 3 of the 19 colonies analyzed a mixture of T(6) positive and T(6) negative karyotypes was present and identical proportions of the karyotypes were present in the pooled B-lymphocyte colony cells and spleen colony cells. The data indicate that the B-lymphocyte colony-forming cells detected in spleen colonies are genuine members of the hemopoietic clone derived from the initiating hemopoietic stem cell (CFU-S).

scholarly journals ONTOGENY OF B-LYMPHOCYTE FUNCTION

1974 ◽  
Vol 140 (5) ◽  
pp. 1285-1302 ◽  
Author(s):  
Edmond A. Goidl ◽  
Gregory W. Siskind
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
B Lymphocytes ◽  
B Lymphocyte ◽  
Fetal Liver ◽  
Lymphoid Tissues ◽  
Lymphocyte Function ◽  
A Cell ◽  
Neonatal Liver ◽  
Thymus Cells

The ontogeny of the ability of B lymphocytes to produce an antihapten response which is heterogeneous with respect to affinity for the antigenic determinant was studied in a cell transfer system. The heterogeneity of affinity of the immune response of lethally irradiated mice reconstituted with syngeneic, adult thymus cells and fetal or neonatal tissues as a source of B lymphocytes was studied. It was found that B cells from 17 day fetal liver or neonatal liver are highly restricted with respect to heterogeneity of affinity as compared with adult spleen or bone marrow. The B-cell population achieves an adult character with respect to heterogeneity of affinity by 2 wk of age. The peripheral lymphoid tissues (spleen) appear to mature in this respect more rapidly than do central lymphoid tissues (bone marrow). Spleens from 10-day old donors behave in an adult, heterogeneous manner while bone marrow from the same donors exhibit a marked restriction in heterogeneity of affinity. Germfree mice produce an immune response which is indistinguishable from conventionally reared adult animals with respect to heterogeneity of affinity. The earlier appearance of the ability to transfer a heterogeneous immune response in spleen as compared with bone marrow suggests that the increasing heterogeneity of the B-lymphocyte population which occurs between birth and 2 wk of age is the result of a differentiation event and not of a somatic mutation or recombination event.

scholarly journals Intrinsic and extrinsic regulation of human fetal bone marrow haematopoiesis and perturbations in Down syndrome

2021 ◽  
Author(s):  
Laura Jardine ◽  
Simone Webb ◽  
Issac Goh ◽  
Mariana Quiroga Londoño ◽  
Gary Reynolds ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Down Syndrome ◽  
B Lymphocyte ◽  
Immune Cell ◽  
Time Window ◽  
Fetal Liver ◽  
Developmental Time ◽  
Chromosome Anomaly ◽  
Postnatal Life ◽  
Cell Repertoire

Throughout postnatal life, haematopoiesis in the bone marrow (BM) maintains blood and immune cell production. Haematopoiesis first emerges in human BM at 12 post conception weeks while fetal liver (FL) haematopoiesis is still expanding. Yet, almost nothing is known about how fetal BM evolves to meet the highly specialised needs of the fetus and newborn infant. Here, we detail the development of fetal BM including stroma using single cell RNA-sequencing. We find that the full blood and immune cell repertoire is established in fetal BM in a short time window of 6-7 weeks early in the second trimester. Fetal BM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell (DC) subsets emerging for the first time. B-lymphocyte expansion occurs, in contrast with erythroid predominance in FL at the same gestational age. We identify transcriptional and functional differences that underlie tissue-specific identity and cellular diversification in fetal BM and FL. Finally, we reveal selective disruption of B-lymphocyte, erythroid and myeloid development due to cell intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in the fetal BM from constitutional chromosome anomaly Down syndrome during this crucial developmental time window.

STAT5 Has Tumor Suppressor-Like Activity in a Murine Model of Myc-Initiated Acute B-Lymphoblastic Leukemia/Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 919-919 ◽  
Author(s):  
Zhengqi Wang ◽  
Geqiang Li ◽  
Zizhen Kang ◽  
Silvia T Bunting ◽  
William Tse ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
B Lymphocyte ◽  
Fetal Liver ◽  
Lymphoblastic Leukemia ◽  
Conditional Knockout ◽  
Lymphocyte Development ◽  
Wild Type ◽  
B Lymphocyte Development ◽  
B Lymphoid

Abstract Abstract 919 Signal transducer and activator of transcription 5 (STAT5) is a critical regulator of normal and leukemic lympho-myeloid hematopoiesis through activation downstream of early-acting cytokines, their receptors, and janus kinases (JAKs). Despite upstream activating mutations driving JAK-STAT phosphorylation in precursor-B acute lymphoblastic leukemia (B-ALL), activated JAK-STAT is absent from the aggressive “double hit” lymphomas expressing myc and bcl-2. Using C57BL/6 background transgenic mouse models for myc and bcl-2, we set out to determine whether endogenous STAT5 functions in guarding against B-ALL induced by combined myc/bcl-2 or myc alone. We first determined whether constitutive expression of bcl-2 driven from the H2K promoter and Moloney murine leukemia virus enhancer in C57BL/6 background STAT5-deficient hematopoietic cells could bypass blocks in B-lymphocyte development. Transgenic H2K/bcl-2 expression in hypomorphic STAT5abDN/DN mice, which are leaky and still produce some mature B-lymphocytes, largely rescued peripheral B-lymphocyte survival to near normal levels but could only rescue about 10% of the multilineage hematopoietic stem cell (HSC) competitive repopulating defect. Complete deletion of the entire STAT5ab locus resulted in the expected severe block of B-cell development at the pre-pro-B-cell stage following transplantation of STAT5ab null/null fetal liver cells into irradiated wild type or common γC−/− recipients. Peripheral B-lymphocyte development could not be restored by transgenic bcl-2 alone in the absence of STAT5. However, transgenic myc driven from an immunoglobulin H chain enhancer (Emu/myc) combined with H2K/bcl-2 induced B-ALL peripheral counts as high as 1.1 × 105 B-cells/ul and reduced latency (a median survival of 44 days) compared to wild-type control (a median survival of 91 days) in either lethally-irradiated (P<0.001; N range from 8–14 mice/group) or sub-lethally-irradiated cohorts of fetal liver transplanted mice (P=0.007; N range 10–20 mice/group). B-ALL in mice with or without STAT5 was a mix of Pro-B and Pre-B ALL (IgM-CD43+B220+CD19+/−CD4+/−) and morphologically similar in the spleen and bone marrow. Multi-parameter flow cytometry analysis of bone marrow cells from STAT5ab null/null fetal liver transplanted mice (N=4) showed that deletion of STAT5 significantly reduced by 11.5-fold (P=0.004) the fraction of long-term repopulating HSC (CD150+CD48-) c-Kit+Lin-Sca-1+ (KLS). In an independent adult Mx1-Cre conditional knockout of STAT5 by pI:pC treatment, lymphomas induced by Myc alone were also accelerated (P=0.05; N range 14–15 mice/group) with STAT5 maintained deleted in sorted B-cells. These mice also had reduced CD150+CD48- KLS cells (5.6-fold; N=4; P=0.006). Interestingly, several phenotypes recently reported as associated with increased HSC cycling and lymphoid-biased differentiation were observed. The mean fluorescence intensity of slamf1 (CD150) was reduced 2.2-fold (P<0.001; N=4) in conditional knockout mice and the B-lymphoid biased CD48+CD150+ or CD48-CD150- KLS cells representing short-term HSC/multipotent progenitors were not significantly reduced. Microarray analyses of the KLS fraction provided evidence that STAT5 promotes HSC maintenance and myeloid potential (limiting lymphoid commitment, cycling) in the KLS compartment. The deletion of STAT5 reduced expression of HSC self-renewal and quiescence promoting genes and increased immunoglobulin and B-lymphoid transcripts. Combined with the pre-pro-B-cell block, loss of STAT5 promotes accumulation of B-lineage committed progenitors as potential ALL initiating cells. The effects of bcl-2 and myc hits on STAT5 null/null hematopoietic cells are currently being further characterized with respect to B-cell developmental blocks and molecular heterogeneity. B-ALL has a high relapse rate and is driven by clonally diverse tumor propagating populations. Our work may have important implications for ALL drug therapy. In conclusion, we demonstrate that STAT5, considered primarily as functioning like an oncogene in hematologic malignancies upon persistent activation, can play a tumor suppressor-like role in subsets of B-ALL. These data add to an emerging understanding that endogenous STAT5 can suppress some cancers and transcriptionally regulate several cell cycle inhibitors. Disclosures: No relevant conflicts of interest to declare.

Developmentally regulated cell surface expression and function of c-kit receptor during lymphocyte ontogeny in the embryo and adult mice

Development ◽  
1992 ◽  
Vol 115 (4) ◽  
pp. 1133-1147 ◽  
Author(s):  
R. Palacios ◽  
S. Nishikawa
Keyword(s):  
Bone Marrow ◽  
Stromal Cells ◽  
B Lymphocyte ◽  
Fetal Liver ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Lymphocyte Development ◽  
Fetal Thymus ◽  
Kit Receptor ◽  
B Lymphocyte Development

We have used a c-kit-specific monoclonal antibody, immuno-fluorescence staining and flow fluorocytometry or microscopy analysis to assess the cell surface expression of the c-kit receptor on a panel of non-transformed clones representing different stages of T- and B-lymphocyte development, freshly isolated lymphoid cells from thymus, bone marrow and spleen of young adult C57BL/6 mice and cells from yolk sac, thymus and liver of developing C57BL/6 mouse embryos. Pro-T, Pro-B and Pre-B clones derived from thymus or liver of 14-day embryos are c-kit+. Starting at day 8 to 8.5 in yolk sac, day-10 in fetal liver, and day 11 to 12 in fetal thymus, there are many c-kit+ cells. The number of c-kit+ cells in liver and thymus increases up to day 15 and progressively decreases thereafter. Cell sorter purified c-kit+ day 14 fetal liver cells fully reconstitute the T and B cell compartments of immunodeficient Scid mice. Stromal cells or epithelial cells derived from fetal thymus or liver, which can support growth and differentiation of c-kit+ lymphocyte progenitor clones, synthesize mRNA for Steel Factor (SF), the ligand of c-kit. In the adult mouse, however, c-kit expression is restricted to very early stages of T- and B-lymphocyte development (multipotent progenitors, B-cell/myelocytic progenitors, Pro-T and Pro-B lymphocyte progenitors). Most cells at the Pre-T, Pre-B and later stages of development do not bear detectable c-kit. Using Cos-1 cells transfected with mouse SF-cDNA and an antagonistic c-kit receptor-specific antibody, we show that the c-kit/SF system contributes to the survival of lymphocyte progenitors and enhances the proliferative responses of these cells to other growth factors (i.e. IL2, IL3, IL4, IL7). However, the c-kit receptor/SF ligand pair is neither sufficient nor necessary for the differentiation of lymphocyte progenitors into mature T- or B-lymphocytes. Finally, in stromal cell lines from fetal liver and adult bone marrow and thymic epithelial cell lines the level of steady state SF-RNA transcripts is inversely correlated with that of IL-7-mRNA. Moreover, IL7 inhibits the synthesis of SF-mRNA in stromal cells and rIL6 abrogates this inhibitory effect of rIL7. Thus, the expression of SF in stromal cells is subjected to complex regulation by other cytokines produced by the same stromal cells or by neighboring cells in a given microenvironment.(ABSTRACT TRUNCATED AT 400 WORDS)

Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1216-1222 ◽  
Author(s):  
Rhodri Ceredig ◽  
Melanie Rauch ◽  
Gina Balciunaite ◽  
Antonius G. Rolink
Keyword(s):  
Bone Marrow ◽  
B Lymphocyte ◽  
Marrow Cell ◽  
Fold Increase ◽  
Inhibitory Effect ◽  
B Lymphopoiesis ◽  
Developmental Potential ◽  
Myeloid Progenitor ◽  
Progenitor Compartment ◽  
Expected Increase

Abstract We have recently described a CD19– B220+CD117low bone marrow subpopulation with B, T, and myeloid developmental potential, which we have called “early progenitors with lymphoid and myeloid potential” or EPLM. These cells also expressed Fms-like tyrosine kinase 3, Flt3, or CD135. Treatment of mice with the corresponding ligand, Flt3L, showed a 50-fold increase in EPLM. In addition to the expected increase in dendritic cell numbers, Flt3L treatment had a reversible inhibitory effect on B lymphopoiesis. Limiting dilution analysis of sorted EPLM from Flt3L-treated mice showed that B-lymphocyte progenitor activity was reduced 20-fold, but that myeloid and T-cell progenitor activity was largely preserved. EPLM from treated mice transiently reconstituted the thymus and bone marrow of recipient mice, generating cohorts of functional T and B cells in peripheral lymphoid organs. Thus, Flt3L treatment results in a dramatic increase in a novel bone marrow cell with lymphoid and myeloid progenitor activity.

scholarly journals Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory, and Foxp3+ T reg induction capacity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cytotoxic T Cells ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Adult Bone

Abstract Background Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

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