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Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand

Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokin...

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Autores principales: Klein, Fabian, von Muenchow, Lilly, Capoferri, Giuseppina, Heiler, Stefan, Alberti-Servera, Llucia, Rolink, Hannie, Engdahl, Corinne, Rolink, Michael, Mitrovic, Mladen, Cvijetic, Grozdan, Andersson, Jan, Ceredig, Rhodri, Tsapogas, Panagiotis, Rolink, Antonius
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191501/
https://www.ncbi.nlm.nih.gov/pubmed/30364182
http://dx.doi.org/10.3389/fimmu.2018.02258
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author Klein, Fabian
von Muenchow, Lilly
Capoferri, Giuseppina
Heiler, Stefan
Alberti-Servera, Llucia
Rolink, Hannie
Engdahl, Corinne
Rolink, Michael
Mitrovic, Mladen
Cvijetic, Grozdan
Andersson, Jan
Ceredig, Rhodri
Tsapogas, Panagiotis
Rolink, Antonius
author_facet Klein, Fabian
von Muenchow, Lilly
Capoferri, Giuseppina
Heiler, Stefan
Alberti-Servera, Llucia
Rolink, Hannie
Engdahl, Corinne
Rolink, Michael
Mitrovic, Mladen
Cvijetic, Grozdan
Andersson, Jan
Ceredig, Rhodri
Tsapogas, Panagiotis
Rolink, Antonius
author_sort Klein, Fabian
collection PubMed
description Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokines. IL-7 is an important survival and proliferation factor for B cell progenitors, whereas FL acts on several early developmental stages, prior to B cell commitment. We have generated mice constitutively over-expressing both IL-7 and FL. These double transgenic mice develop splenomegaly and lymphadenopathy characterized by tremendously enlarged lymph nodes even in young animals. Lymphoid, myeloid and dendritic cell numbers are increased compared to mice over-expressing either of the two cytokines alone and the effect on their expansion is synergistic, rather than additive. B cell progenitors, early progenitors with myeloid and lymphoid potential (EPLM), common lymphoid progenitors (CLP) and lineage(−), Sca1(+), kit(+) (LSK) cells are all increased not only in the bone marrow but also in peripheral blood, spleen and even lymph nodes. When transplanted into irradiated wild-type mice, lymph node cells show long-term multilineage reconstitution, further confirming the presence of functional hematopoietic progenitors therein. Our double transgenic mouse model shows that sustained and combined over-expression of IL-7 and FL leads to a massive expansion of most bone marrow hematopoietic progenitors and to their associated presence in peripheral lymphoid organs where they reside and potentially differentiate further, thus leading to the synergistic increase in mature lymphoid and myeloid cell numbers. The present study provides further in vivo evidence for the concerted action of IL-7 and FL on lymphopoiesis and suggests that extramedullary niches, including those in lymph nodes, can support the survival and maintenance of hematopoietic progenitors that under physiological conditions develop exclusively in the bone marrow.
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spelling pubmed-61915012018-10-24 Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand Klein, Fabian von Muenchow, Lilly Capoferri, Giuseppina Heiler, Stefan Alberti-Servera, Llucia Rolink, Hannie Engdahl, Corinne Rolink, Michael Mitrovic, Mladen Cvijetic, Grozdan Andersson, Jan Ceredig, Rhodri Tsapogas, Panagiotis Rolink, Antonius Front Immunol Immunology Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokines. IL-7 is an important survival and proliferation factor for B cell progenitors, whereas FL acts on several early developmental stages, prior to B cell commitment. We have generated mice constitutively over-expressing both IL-7 and FL. These double transgenic mice develop splenomegaly and lymphadenopathy characterized by tremendously enlarged lymph nodes even in young animals. Lymphoid, myeloid and dendritic cell numbers are increased compared to mice over-expressing either of the two cytokines alone and the effect on their expansion is synergistic, rather than additive. B cell progenitors, early progenitors with myeloid and lymphoid potential (EPLM), common lymphoid progenitors (CLP) and lineage(−), Sca1(+), kit(+) (LSK) cells are all increased not only in the bone marrow but also in peripheral blood, spleen and even lymph nodes. When transplanted into irradiated wild-type mice, lymph node cells show long-term multilineage reconstitution, further confirming the presence of functional hematopoietic progenitors therein. Our double transgenic mouse model shows that sustained and combined over-expression of IL-7 and FL leads to a massive expansion of most bone marrow hematopoietic progenitors and to their associated presence in peripheral lymphoid organs where they reside and potentially differentiate further, thus leading to the synergistic increase in mature lymphoid and myeloid cell numbers. The present study provides further in vivo evidence for the concerted action of IL-7 and FL on lymphopoiesis and suggests that extramedullary niches, including those in lymph nodes, can support the survival and maintenance of hematopoietic progenitors that under physiological conditions develop exclusively in the bone marrow. Frontiers Media S.A. 2018-10-10 /pmc/articles/PMC6191501/ /pubmed/30364182 http://dx.doi.org/10.3389/fimmu.2018.02258 Text en Copyright © 2018 Klein, von Muenchow, Capoferri, Heiler, Alberti-Servera, Rolink, Engdahl, Rolink, Mitrovic, Cvijetic, Andersson, Ceredig, Tsapogas and Rolink. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Klein, Fabian
von Muenchow, Lilly
Capoferri, Giuseppina
Heiler, Stefan
Alberti-Servera, Llucia
Rolink, Hannie
Engdahl, Corinne
Rolink, Michael
Mitrovic, Mladen
Cvijetic, Grozdan
Andersson, Jan
Ceredig, Rhodri
Tsapogas, Panagiotis
Rolink, Antonius
Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand
title Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand
title_full Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand
title_fullStr Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand
title_full_unstemmed Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand
title_short Accumulation of Multipotent Hematopoietic Progenitors in Peripheral Lymphoid Organs of Mice Over-expressing Interleukin-7 and Flt3-Ligand
title_sort accumulation of multipotent hematopoietic progenitors in peripheral lymphoid organs of mice over-expressing interleukin-7 and flt3-ligand
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191501/
https://www.ncbi.nlm.nih.gov/pubmed/30364182
http://dx.doi.org/10.3389/fimmu.2018.02258
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