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Knock Knock Knock, Who is there? - Cell Crosstalk within the Bone Marrow
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-72336ISBN: 978‐91‐7393‐016‐1 OAI: oai:DiVA.org:liu-72336DiVA: diva2:459205
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: 2012-01-18Bibliographically approved
List of papers
1. IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
Open this publication in new window or tab >>IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
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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
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70104 (URN)10.1182/blood-2011-01-332189 (DOI)000293510000020 ()
Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08
2. The Cxcl12, Periostin, and Ccl9 genes are direct targets for early B-cell factor in OP-9 stroma cells
Open this publication in new window or tab >>The Cxcl12, Periostin, and Ccl9 genes are direct targets for early B-cell factor in OP-9 stroma cells
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2007 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, no 19, 14454-14462 p.Article in journal (Refereed) Published
Abstract [en]

The development of blood cells from hematopoietic stem cells in the bone marrow is dependent on communication with bone marrow stroma cells, making these cells central for the appropriate regulation of hematopoiesis. To identify transcription factors that may play a role in gene regulation in stroma cells, we performed comparative gene expression analysis of fibroblastic NIH3T3 cells, unable to support hematopoiesis in vitro, and OP-9 stroma cells, highly efficient in this regard. These experiments revealed that transcription factors of the early B cell factor (EBF) family were highly expressed in OP-9 cells as compared with the NIH3T3 cells. To identify potential targets genes for EBF proteins in stroma cells, we overexpressed EBF in fibroblasts and analyzed the pattern of induced genes by microarray analysis. This revealed that EBF was able to up-regulate expression of among others the Cxcl12, Ccl9, and Periostin genes. The identification of relevant promoters revealed that they all contained functional EBF binding sites able to interact with EBF in OP-9 cells. Furthermore, ectopic expression of a dominant negative EBF protein or antisense EBF-1 RNA in OP-9 stroma cells resulted in reduced expression of these target genes. These data suggest that EBF proteins might have dual roles in hematopoiesis acting both as intrinsic regulators of B-lymphopoiesis and as regulators of genes in bone marrow stroma cells. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-39974 (URN)10.1074/jbc.M610263200 (DOI)51893 (Local ID)51893 (Archive number)51893 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
3. Genomics based analysis of interactions between developing B-lymphocytes and stromal cells reveal complex interactions and two-way communication
Open this publication in new window or tab >>Genomics based analysis of interactions between developing B-lymphocytes and stromal cells reveal complex interactions and two-way communication
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2010 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 11, no 108Article in journal (Refereed) Published
Abstract [en]

Background: The use of functional genomics has largely increased our understanding of cell biology and promises to help the development of systems biology needed to understand the complex order of events that regulates cellular differentiation in vivo. One model system clearly dependent on the integration of extra and intra cellular signals is the development of B-lymphocytes from hematopoietic stem cells in the bone marrow. This developmental pathway involves several defined differentiation stages associated with specific expression of genes including surface markers that can be used for the prospective isolation of the progenitor cells directly from the bone marrow to allow for ex vivo gene expression analysis. The developmental process can be simulated in vitro making it possible to dissect information about cell/cell communication as well as to address the relevance of communication pathways in a rather direct manner. Thus we believe that B-lymphocyte development represents a useful model system to take the first steps towards systems biology investigations in the bone marrow. Results: In order to identify extra cellular signals that promote B lymphocyte development we created a database with approximately 400 receptor ligand pairs and software matching gene expression data from two cell populations to obtain information about possible communication pathways. Using this database and gene expression data from NIH3T3 cells (unable to support B cell development), OP-9 cells (strongly supportive of B cell development), pro-B and pre-B cells as well as mature peripheral B-lineage cells, we were able to identify a set of potential stage and stromal cell restricted communication pathways. Functional analysis of some of these potential ways of communication allowed us to identify BMP-4 as a potent stimulator of B-cell development in vitro. Further, the analysis suggested that there existed possibilities for progenitor B cells to send signals to the stroma. The functional consequences of this were investigated by co-culture experiments revealing that the co-incubation of stromal cells with B cell progenitors altered both the morphology and the gene expression pattern in the stromal cells. Conclusions: We believe that this gene expression data analysis method allows for the identification of functionally relevant interactions and therefore could be applied to other data sets to unravel novel communication pathways.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-54511 (URN)10.1186/1471-2164-11-108 (DOI)000275293200001 ()
Note
Original Publication: Jenny Zetterblad, Hong Qian, Sasan Zandi, Robert Mansson, Anna Lagergren, Frida Hansson, David Bryder, Nils Paulsson and Mikael Sigvardsson, Genomics based analysis of interactions between developing B-lymphocytes and stromal cells reveal complex interactions and two-way communication, 2010, BMC GENOMICS, (11), 108. http://dx.doi.org/10.1186/1471-2164-11-108 Licensee: BioMed Central http://www.biomedcentral.com/ Available from: 2010-03-19 Created: 2010-03-19 Last updated: 2017-12-12Bibliographically approved
4. Dynamic crosstalk between developing blood cells and mesenchymal stroma compartments
Open this publication in new window or tab >>Dynamic crosstalk between developing blood cells and mesenchymal stroma compartments
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The development of hematopoietic cells in the bone marrow is dependent on cellular interactions between blood cell progenitors and mesenchymal stroma cells. In order to increase the understanding of how cells communicate in this specialized environment, we have developed software scripts that allow us to compare gene expression patterns in two cells types and extract information about potential interaction pathways. The gene expression data was generated from freshly isolated FACS purified BM cells of hematopoietic or mesenchymal origins. This proposed that defined mesenchymal populations provide specific components to the microenvironment. Furthermore, even though several communication pathways were shared by multiple hematopoietic developmental stages, stage specific interactions may be involved in the modulation of defined progenitor populations. Additionally the analysis suggested that there existed possibilities for the hematopoietic cells to signal to the stroma cells and for the stroma cells to signal to each other. Our analysis suggests existence of a highly complex and dynamic crosstalk in the BM microenvironment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72334 (URN)
Available from: 2011-11-25 Created: 2011-11-25 Last updated: 2011-11-25Bibliographically approved

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