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IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
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2011 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 5, 1283-1290 p.Article in journal (Refereed) Published
Abstract [en]

eficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D(-) multipotent CLPs, the formation of the lineage restricted LY6D(+) CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D(+) CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D(+) cells develop in Ebf-1-deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D(+) CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.

Place, publisher, year, edition, pages
American Society of Hematology , 2011. Vol. 118, no 5, 1283-1290 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-70104DOI: 10.1182/blood-2011-01-332189ISI: 000293510000020OAI: oai:DiVA.org:liu-70104DiVA: diva2:435548
Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08
In thesis
1. Knock Knock Knock, Who is there? - Cell Crosstalk within the Bone Marrow
Open this publication in new window or tab >>Knock Knock Knock, Who is there? - Cell Crosstalk within the Bone Marrow
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is focused on the subject of cell-cell interaction. Our body is composed of cells, most of them are integrated in a network with other cells that together forms tissues and organs. Every cell type in these complex organs has its special task and location. This is true whether we are doing research on humans or, as we have been, investigating mice. Mice are excellent models for studies of blood cell development since this process in mice resembles human blood cell generation in many regards.

Cells communicate with each other by sending out small molecules or by directly binding to surrounding cells; to cells of the same kind as well as to cells with different origins and tasks. A cell is surrounded by hundreds of different signal-carrying entities; soluble, bound to the extra cellular matrix or bound to its surface. Every cell has to distinguish and respond to the environment according to its own specific nature.

In the first article interleukin 7 (IL-7) a growth factor expressed by the stroma cells was studied. Results show that IL-7 is crucial for the immature progenitor cell in its development towards antibody producing B-lymphocytes. The second article is about stroma cells and their ability to support the development of B-cells. It is a comparative study on two different cell lines, where we focus on transcription factors and their regulation of protein induction of factors supporting B-cells. This study increased our knowledge of stroma cells. In the third paper we combined our knowledge from the first two papers in regard to stroma cells as well as B-cell development by testing if there is a possibility to theoretically find new factors of importance for the maturing B-cell. We achieved this by the development of GCINT, a database investigating possible receptorligand interactions between two cells, verifying these results in vitro with cell lines as well as primary cells. This revealed a two way communication between blood cells and stroma cells, highlighting the complexity of the bone marrow environment. In the last article we continued this work with primary FACS sorted stroma cells investing the potential connections between each of the stroma cell populations with primary blood cells in different stages of development. This work supports a model where hematopoietic cells can interact with stroma cells in a stage-specific manner and that the exchange between cells is of importance for their maturation.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1280
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72336 (URN)9789173930161 (ISBN)
Public defence
2011-12-15, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2011-11-25 Created: 2011-11-25 Last updated: 2017-12-18Bibliographically approved
2. Molecular mechanisms in lymphoid restriction: securing the B lineage fate
Open this publication in new window or tab >>Molecular mechanisms in lymphoid restriction: securing the B lineage fate
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

With the work in this thesis I have aimed to deepen the understanding of the mechanisms behind the development of different blood cell lineages with a specific focus on B cell development.

To understand the interplay between extracellular signaling and transcription factor networks in early lymphoid development we investigated the functional collaborations of FLT3 and IL7R. We found that signaling via FLT3 and IL7R act in powerful synergy on proliferation of common lymphoid progenitors (CLPs). In addition to a role in expansion of progenitor cells we provided evidence for that IL7R signaling play a crucial role in B-cell commitment. IL7 deficient mice display a dramatic block in development before functional lineage restriction in the Ly6D+ CLP-compartment. The few Ly6D+CLPs that do develop have reduced mRNA levels of transcription factor EBF1, a protein with crucial functions in lineage restriction and activation of the B-lymphoid program. One crucial function of EBF1 is to activate Pax5. Even though Pax5 deficient fetal liver cells upon transplantation to congenic hosts will generate an abundance of cells with an activated B-lineage transcriptional program, the pro-B cells have disrupted regulation of non-B-lineage transcripts and a propensity to develop into T- and NK-cells in vitro. Both the activation of the B-lineage program and lineage restriction was dependent on the dose of transcription factors. Mice carrying a heterozygous mutation for the transcription factor E2A had slightly reduced relative frequency of progenitor cells and an impaired B-lineage specification in CLPs. Loss of one allele of Ebf1 resulted in reduced surface expression of IL2Rα and pre-B cell receptor (BCR), reduced IL7-response in vitro, and disrupted cell cycle dynamics in pro- and pre-B cells. While heterozygous loss of Pax5 did not result in any dramatic phenotype,  the combined loss of one allele of Pax5 and one allele of Ebf1 (Pax5+/-Ebf1+/-) had a dramatic effect on lineage plasticity in B-cell progenitors compared to the single heterozygotes. Furthermore, these Pax5+/-Ebf1+/- mice developed spontaneous, transplantable pro-B cell tumors and had a significantly reduced probability to survive over time. The transformed cells show high in vitro plasticity and tumor cells with induced overexpression of intracellular Notch1 can transform into T-lineage cell in vivo.

The data presented in this thesis add important pieces of information to the field of developmental hematopoiesis. By increasing the analytical depth of development in normal circumstances, and by understanding the consequence of genetic mutations in relation to cell type, we hope to contribute to the understanding of hematopoietic development in health and disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 55 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1422
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-114273 (URN)10.3384/diss.diva-114273 (DOI)978-91-7519-226-0 (ISBN)
Public defence
2014-12-12, Victoriasalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2016-06-22Bibliographically approved

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Tsapogas, PanagiotisZandi, SasanÅhsberg, JosefineZetterblad, JennyWelinder, EvaJönsson, Jan-IngvarQian, HongSigvardsson, Mikael

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