T Cell Progenitors in the Murine Fetal Liver: Differences from Those in the Adult Bone Marrow

1997 ◽  
Vol 177 (1) ◽  
pp. 18-25 ◽  
Author(s):  
Yoshihiro Watanabe ◽  
Yuichi Aiba ◽  
Yoshimoto Katsura
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Fetal Liver ◽  
Adult Bone Marrow ◽  
T Cell Progenitors ◽  
Adult Bone

NOTCH1 Induces Differential Epigenomic Patterning and Genomic Organization in Fetal Liver- and Adult Bone Marrow-Derived Hematopoietic Progentiors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3637-3637
Author(s):  
Vincenzo Giambra ◽  
Sonya H Lam ◽  
Miriam Belmonte ◽  
Sam Gusscott ◽  
Sohrab Salehi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Promoter Region ◽  
Fetal Liver ◽  
Lymphoblastic Leukemia ◽  
Chromosome Conformation Capture ◽  
Chromosome Conformation ◽  
Hematopoietic Stem ◽  
Adult Bone Marrow ◽  
Adult Bone

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T-cell progenitors, characterized by activating NOTCH1 mutations in over 50% of children and adult cases. Although intensive multiagent chemotherapy achieves cure in most pediatric patients, the majority of adults succumb quickly to their disease. The basis for this divergence is likely multifactorial, but we sought in this study to investigate whether cell intrinsic features might contribute to the disparate biologies in pediatric and adult patients. In our prior abstract, we modeled pediatric and adult leukemias by transduction of hematopoietic stem/progenitor cells (HSPC) derived from mouse fetal liver (FL) and adult bone marrow (ABM) with activated NOTCH1 virus followed by transplantation into histocompatible recipient animals. We observed that whereas FL- and ABM-derived HSPC generate similar primary acute T-cell leukemias in terms of penetrance, latency, disease burden/distribution, and immunophenotype, FL leukemias exhibit much greater cycling activity than ABM leukemias, yet are dramatically impaired in their ability to propagate disease in secondary and tertiary recipients compared to ABM leukemias. Using a combination of gene expression profiling and in vitro culture assays, we attributed this differential behavior to NOTCH1-induced autocrine IGF signaling that is operative in FL, but not ABM-derived HSPC. Here we report that NOTCH1 mediates its effects on IGF1 in FL-derived HSPC directly by physical occupancy over the IGF1 promoter in a dimerization-dependent fashion. As well, increased NOTCH1 occupancy at the IGF1 promoter region in FL tissues is associated with reduced histone H3K27 trimethylation (a mark of transcriptionally silent chromatin), yet there is equivalent histone H3K4 trimethylation (a mark identifying transcriptionally active promoters) in both FL and ABM tissues, suggesting that NOTCH1 may be responsible for interconverting the IGF1 locus between active and inactive, but poised chromatin states. NOTCH1 occupancy is also associated with enhanced physical interactions between the IGF1 promoter region and distant genomic loci as revealed by circularized chromosome conformation capture (4C) assay and confirmed by chromosome conformation capture (3C) assay, including sites with H3K4 monomethylation (a mark of transcriptional enhancers) suggesting that NOTCH1 promotes "looping in" of distant enhancer elements that drive IGF1 expression in FL tissues. We conclude from these studies that NOTCH1 enacts differential, developmental stage-specific transcriptional programs by a combination of local epigenetic patterning and long-range genomic interactions. These findings support the notion that pediatric and adult T-ALL may potentially be regarded as related, but biologically distinct diseases, and that novel, age-specific therapies that exploit these differences may improve clinical outcomes. Disclosures No relevant conflicts of interest to declare.

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

2020 ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Wide Range ◽  
Adult Bone

Abstract Background: Mesenchymal stem cells (MSCs) display active capacities of suppressing or modulating harmful immune responses through diverse molecular mechanisms. These cells are under extensive translational efforts as cell therapies for immune-mediated diseases and transplantations. A wide range of preclinical studies and limited number of clinical trials using MSCs have not only shown promising safety and efficacy profiles but have also revealed changes in regulatory T cell (T reg) frequency and function. However, the mechanisms underlying this important observation are not well understood. Cell-to-cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes have emerged as possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion. 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 induction of Tregs. In parallel we demonstrated that fetal liver (FL)-MSCs displays 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 exhibit similar 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.

scholarly journals Human Fetal Liver MSCs are More Effective Than Adult Bone Marrow MSCs for Their Immunosuppressive, Immunomodulatory and Foxp3+ T regs Induction Capacity

2020 ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Wide Range ◽  
Adult Bone

Abstract Background: Mesenchymal stem cells (MSCs) display active capacities of suppressing or modulating harmful immune responses through diverse molecular mechanisms. These cells are under extensive translational efforts as cell therapies for immune-mediated diseases and transplantations. A wide range of preclinical studies and limited number of clinical trials using MSCs have not only shown promising safety and efficacy profiles but have also revealed changes in regulatory T cell (T reg) frequency and function. However, the mechanisms underlying this important observation are not well understood. Cell-to-cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes have emerged as possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion. 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 induction of Tregs. In parallel we demonstrated that fetal liver (FL)-MSCs displays 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 exhibit similar phenotype 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.

Fetal Vs. Adult Hematopoietic Progenitors Respond Differently to NOTCH1: Implications for Pediatric Vs. Adult T-ALL.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2381-2381
Author(s):  
Vincenzo Giambra ◽  
Sonya H Lam ◽  
Amy Ng ◽  
Claudia Benz ◽  
Olena O Shevchuk ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Lymphoblastic Leukemia ◽  
Mouse Bone Marrow ◽  
Hematopoietic Stem ◽  
Adult Bone Marrow ◽  
Old Adult ◽  
Adult Bone

Abstract Abstract 2381 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T-cell progenitors which affects both children and adults. Whereas pediatric T-ALL is curable in 80–90% of cases, only 40% of adults with T-ALL survive beyond 5 years. Fetal liver and adult bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) are known to differ in terms of their gene expression programs and functional properties. Despite this work, the extent to which differential programming of fetal and adult HSPCs may impact the biology of their respective leukemias in children and adults remains unexplored. NOTCH1 is a prominent oncogene in T-ALL and activated by mutation in over 50% of cases. The retroviral NOTCH1 mouse bone marrow transplant model of T-ALL is well established; however, most investigators use 8–12 week-old adult mice as bone marrow donors for these experiments and thus these studies could be interpreted as having modeled adult disease. In order to explore the possibility that fetal program HSPCs would more accurately model pediatric disease, we transduced lineage-negative fetal liver HSPCs with activated NOTCH1 (ΔE) retrovirus, transplanted them into syngeneic (C57BL/6) recipients, and compared the behavior of the resulting leukemias to those generated from lineage-negative 8-week-old adult bone marrow HSPCs. Primary transplant recipient mice developed nearly identical T-ALL disease in terms of penetrance, latency, disease distribution/burden, and immunophenotype. Serial transplantation of these leukemias into secondary recipients, however, revealed stark differences in that whereas “adult” leukemias were readily transplantable, “fetal” leukemias were largely non-transplantable. In order to quantitate leukemia-initiating cell (LIC) frequencies in these two situations, we performed secondary transplants into highly permissive, immunodeficient (NOD/Scid/Il2rg−/−) recipients at limiting dilution and observed fetal leukemias to exhibit 500-fold lower LIC activity than adult leukemias (1 in ∼4500 cells vs. 1 in ∼9 cells, respectively). To identify potential mechanisms that might underlie this difference in LIC activity, we compared the behaviors of fetal liver vs. adult bone marrow-derived HSPCs shortly after transduction with NOTCH1(ΔE) virus. Interestingly, NOTCH1 induced fetal HSPCs to cycle rapidly whereas adult HSPCs were largely quiescent. We also noted that non-transduced cells in fetal HSPC cultures were also cycling rapidly, and through a series of fetal/adult mixing and conditioned media experiments, we determined that NOTCH1 induces an autocrine IGF1 signaling circuit in fetal, but not adult HSPCs. This observation was also confirmed to hold true for CD34+ human cord blood vs. adult bone marrow HSPCs. Expression profiling/qRT-PCR and chromatin immunoprecipitation (ChIP) studies further revealed NOTCH1 to induce IGF1 transcription and altered chromatin structure (increased H3K4me3 and decreased H3K27me3 marks) specifically in fetal, but not adult HSPCs. These findings suggest that developmental stage-specific programming in fetal vs. adult progenitors underlies their differential responses to oncogenic NOTCH1 signaling, and also the biological aggressiveness of resulting leukemias. Therapeutic targeting of adult-specific pathways may thus achieve improved clinical responses in adults with T-ALL and perhaps also the minority of pediatric patients with more aggressive, possibly “adult-like” disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The junctional modifications of a T cell receptor gamma chain are determined at the level of thymic precursors.

1991 ◽  
Vol 174 (5) ◽  
pp. 1279-1282 ◽  
Author(s):  
K Ikuta ◽  
I L Weissman
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
Bone Marrow Cells ◽  
Fetal Liver ◽  
Cell Receptor ◽  
Adult Bone Marrow ◽  
Nucleotide Insertion ◽  
Adult Bone ◽  
Marrow Cells

T precursors from fetal liver and adult bone marrow were compared for their ability to give rise to V gamma 4+ T cell development. Fetal thymic lobes were repopulated with fetal liver or adult bone marrow cells, and the organ-cultured thymocytes were analyzed for their T cell receptor expression by the polymerase chain reaction (PCR). Both day 14 fetal liver and adult bone marrow cells gave rise to thymocytes with V gamma 4-J gamma 1 transcripts. However, the average size of the PCR products derived from adult precursors was slightly larger than that from fetal precursors. DNA sequence analysis of the V gamma 4-J gamma 1 transcripts showed that early fetal liver precursors predominantly gave rise to thymocytes with the V gamma 4-J gamma 1 transcripts without N nucleotide insertion, while late fetal liver and adult marrow precursors predominantly gave rise to thymocytes with modified V gamma 4-J gamma 1 junctions. These results suggest the possibility that the level of the N nucleotide insertion is programmed at the level of thymic precursors. This study also supported the model presented previously that the developmental potential of hematopoietic stem cells may change during ontogeny.

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.

scholarly journals Chromatin structure and developmental expression of the human alpha-globin cluster.

1986 ◽  
Vol 6 (4) ◽  
pp. 1108-1116 ◽  
Author(s):  
M Yagi ◽  
R Gelinas ◽  
J T Elder ◽  
M Peretz ◽  
T Papayannopoulou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chromatin Structure ◽  
Bone Marrow Cells ◽  
Fetal Liver ◽  
Globin Gene ◽  
Erythroid Cells ◽  
Adult Bone Marrow ◽  
Hypersensitive Sites ◽  
Alpha Globin ◽  
Adult Bone

The human alpha-like globins undergo a switch from the embryonic zeta-chain to the alpha-chain early in human development, at approximately the same time as the beta-like globins switch from the embryonic epsilon-to the fetal gamma-chains. We investigated the chromatin structure of the human alpha-globin gene cluster in fetal and adult erythroid cells. Our results indicate that DNase I-hypersensitive sites exist at the 5' ends of the alpha 1- and alpha 2-globin genes as well as at several other sites in the cluster in all erythroid cells examined. In addition, early and late fetal liver erythroid cells and adult bone marrow cells contain hypersensitive sites at the 5' end of the zeta gene, and in a purified population of 130-day-old fetal erythroid cells, the entire zeta-to alpha-globin region is sensitive to DNase I digestion. The presence of features of active chromatin in the zeta-globin region in fetal liver and adult bone marrow cells led us to investigate the transcription of zeta in these cells. By nuclear runoff transcription studies, we showed that initiated polymerases are present on the zeta-globin gene in these normal erythroid cells. Immunofluorescence with anti-zeta-globin antibodies also showed that late fetal liver cells contain zeta-globin. These findings demonstrate that expression of the embryonic zeta-globin continues at a low level in normal cells beyond the embryonic to fetal globin switch.

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