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B-lineage commitment prior to surface expression of B220 and CD19 on hematopoietic progenitor cells
Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
Hematopoietic Stem Cell Laboratory Lund University, Sweden.
Laboratory of Lymphocyte Signaling and Development The Babraham Institute, Cambridge, United Kingdom.
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2008 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 112, no 4, 1048-1055 p.Article in journal (Refereed) Published
Abstract [en]

Commitment of hematopoietic progenitor cells to B-lymphoid cell fate has been suggested to coincide with the development of PAX5-expressing B220 +CD19+ pro-B cells. We have used a transgenic reporter mouse, expressing human CD25 under the control of the B-lineage- restricted IgII1 (λ5) promoter to investigate the lineage potential of early progenitor cells in the bone marrow. This strategy allowed us to identify a reporter expressing LIN-B220- CD19-CD127 +FLT3+ SCA1lowKITlow population that displays a lack of myeloid and a 90% reduction in in vitro T-cell potential compared with its reporter-negative counterpart. Gene expression analysis demonstrated that these lineage-restricted cells express B- lineage-associated genes to levels comparable with that observed in pro-B cells. These data suggest that B-lineage commitment can occur before the expression of B220 and CD19. © 2008 by The American Society of Hematology.

Place, publisher, year, edition, pages
2008. Vol. 112, no 4, 1048-1055 p.
Keyword [en]
Animals Antigens, CD19/*analysis Antigens, CD45/*analysis B-Lymphocytes/chemistry/*cytology Bone Marrow Cells *Cell Lineage Hematopoietic Stem Cells/chemistry/*cytology Humans Interleukin-2 Receptor alpha Subunit Mice Mice, Inbred C57BL Mice, Transgenic
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-43397DOI: 10.1182/blood-2007-11-125385Local ID: 73745OAI: diva2:264256
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2010-11-17
In thesis
1. What’s in a name?: Sub-fractionation of common lymphoid progenitors
Open this publication in new window or tab >>What’s in a name?: Sub-fractionation of common lymphoid progenitors
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The hematopoietic system is a highly dynamic organ developed in many multi-cellular organisms to provide oxygen, prevent bleeding and to protect against microorganisms. The blood consist of many different specialized cells that all derive from rare hematopoietic stem cells (HSCs) located in the bone marrow in mice and humans. Blood cell production from HSCs occurs in a stepwise manner through development of intermediate progenitors that gradually loose lineage potentials. This is a tightly regulated process with complex regulatory mechanisms and many checkpoints that ensure a high and balanced production of blood cells. One of the fundamental questions in hematopoiesis relates to how the maturation of the cells is controlled and driven towards defined cell fates. The understanding of these processes is largely facilitated by isolation of intermediate populations of cells at defined stages of development.

This thesis is focused on the regulatory mechanisms that regulate the maturation of B-lymphocytes constituting an important part of adaptive immunity by being responsible for the production of antibodies. It has been suggested that all the lymphoid cells have a common lineage restricted ancestor defined as a Lin-KitloSca1loFlt3+IL7R+ common lymphoid progenitor (CLP). These cells are believed retain the combined potentials for B, T and NK cells and it has been presumed that commitment of CLPs to B lineage is associated with expression of CD19 and B220 on progenitor B-cells.

The aim of this thesis has been to identify the point of no return in B-cell development in order to allow for a better understanding of lineage restriction events in early lymphopoesis.

To this end, we have used reporter transgenic mice where marker gene expression has been controlled by the transcription regulatory elements from one early lymphoid marker (Rag1) and one B-lymphoid restricted gene (λ5, Igll1). This allowed us to identify three functionally distinct sub-populations within the conventional CLP compartment. The cells were identified as CLPRaglowλ5- cells retaining B, T, Nk and a limited myeloid potential while up-regulation of Rag1 to generate CLPRaghighλ5- cells, was associated with loss of Nk potential as well as of the residual myeloid potential. Ultimately expression of λ5 in the CLPRag1highλ5+ compartment identifies the first committed B cells. Hence, our data suggest that the point of no return in B-cell development can be found within the CD19- CLP compartment. Using this new model for B-cell development, we investigated the instructive vs. permissive role of IL7 signaling in B cell commitment. Our results show that in absence of IL7, CLP maturation is impaired and generation of the earliest committed B-lineage cells is severely impaired. CLP maturation could not be rescued by ectopic expression of the anti-apoptotic Bcl2 protein even though the cells were able to generate normal B lineage cells after restoration of the IL7 signal. These findings suggest that Il7 is crucial for the maturation of lineage restricted CLPs and provide support for an instructive role of IL7 in early Bcell development.

This thesis highlights the importance of precise identification of the point of commitment in B cell development and provides insight to the hematopoietic hierarchical model with the potential to serve as a map to better understand the mechanisms of hematopoietic disorders.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2010. 57 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1214
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-61590 (URN)978-91-7393-284-4 (ISBN)
Public defence
2010-11-29, Linden, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (English)
Available from: 2010-11-17 Created: 2010-11-17 Last updated: 2010-12-14Bibliographically approved

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Zandi, SasanSigvardsson, Mikael
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