To be or not to be, unraveling molecular mechanisms for lineage decisions in developing blood cells
(2007)- Abstract
- All hematopoietic cells originate from hematopoietic stem cells (HSC) residing in the BM. The process of differentiation, through which HSCs generate progenitors and subsequently mature blood cells has been extensively studied but many of the regulatory mechanisms involved remains elusive. The classical model for hematopoiesis has been established based on the identification of common myeloid precursors and common lymphoid precursors, suggesting that the first lineage commitment step results in the strict separation between the lymphoid and myeloid lineages. However, by subfractionation of the LIN-SCA1+KIT+ bone marrow population, containing all HSCs in the mouse, based on expression of CD34 and FLT3, three functionally distinct... (More)
- All hematopoietic cells originate from hematopoietic stem cells (HSC) residing in the BM. The process of differentiation, through which HSCs generate progenitors and subsequently mature blood cells has been extensively studied but many of the regulatory mechanisms involved remains elusive. The classical model for hematopoiesis has been established based on the identification of common myeloid precursors and common lymphoid precursors, suggesting that the first lineage commitment step results in the strict separation between the lymphoid and myeloid lineages. However, by subfractionation of the LIN-SCA1+KIT+ bone marrow population, containing all HSCs in the mouse, based on expression of CD34 and FLT3, three functionally distinct populations were identified. CD34- cells contained the HSCs, CD34+FLT3- short term repopulating cells and CD34+ FLT3+/hi cells with combined lymhpoid and GM potential but, only a small fraction (3%) displaying MkE potential in vitro. In agreement with this MkE associated genes (Gata1, Epor, Vwf etc) were found to be down-regulated in CD34+FLT3hi cells while lymphoid associated genes (Il7r, Rag1, Tdt, sterile IgH transcripts) were found to be up-regulated both at the population and single cell level. Based on this we proposed a new model for hematopoietic development were the first restriction point involves the separation of MkE and lymphoid potential while retaining GM potential. In order to investigate the continued development of B-lymphoid cells we investigated the functional role of the transcription factor EBF1, known to be of critical importance for B cell development. By means of comparativ and correlativ analysis of microarray data from cell-lines we, in addition to the previously known EBF1 target genes, identified Vpreb3, CD19, Ceacam1 and CD53 as EBF1 target genes. Furthermore, by transplantations of EBF1 deficient fetal liver cells, we were able to show EBF1 to be dispensable for the generation of CLPs but that lack of EBF1 expression resulted in diminished IgH DJ recombination and reduced expression of B-lineage associated genes already at this early stage of development. Using a hCD25 lambda5-promoter transgene as a marker for EBF1 activity a small CLP subpopulation (~6%) could be identified. This population demonstrated diminished T-cell potential, increased B-cell potential, as well as up-regulation of Vpreb, lambda5, B29, Mb1 and importantly Pax5. Taken together this suggest that B-lineage commitment occurs already at the level of the CLP. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/598830
- author
- Månsson, Robert LU
- supervisor
- opponent
-
- Professor Singh, Harinder, Howard Hughes Medical Institute, University of Chicago
- organization
- publishing date
- 2007
- type
- Thesis
- publication status
- published
- subject
- keywords
- Hematologi, extracellular fluids, Haematology, common lymphoid precursor (CLP), early B-cell factor 1 (EBF1), B-cell, Stemcell, hematopoiesis, extracellulära vätskor, Immunology, serology, transplantation, Immunologi, serologi
- pages
- 130 pages
- publisher
- Lund University: Faculty of Medicine
- defense location
- Segerfalksalen WNC Sölvegatan 17 Lund
- defense date
- 2007-09-21 13:00:00
- ISBN
- 978-91-85897-06-3
- language
- English
- LU publication?
- yes
- additional info
- Robert Månsson, Panagiotis Tsapogas, Mikael Åkerlund, Anna Lagergren, Ramiro Gisler and Mikael Sigvardsson. 2004. Pearson correlation analysis of microarray data allows for the identification of genetic targets for early B-cell factor. Journal of Biological Chemistry, vol 279 pp 17905-17913. Lund University, Faculty of MedicinRobert Månsson, Anna Lagergren, Frida Hansson, Emma Smith and Mikael Sigvardsson. 2007. The CD53 and CEACAM-1 genes are genetic targets for early B-cell factor. European Journal of Immunology, vol 37 pp 1365-1376. Lund University, Faculty of MedicinRobert Månsson, Inga-Lill Mårtensson, Sten Eirik Jacobsen, Rudolf Grosschedl, David Bryder and Mikael Sigvardsson. . Functional expression of early B-cell factor 1 (EBF1) is associated with lineage restriction of common lymphoid progenitors. Lund University, FAculty of Medicin (submitted)Jörgen Adolfsson, Robert Månsson, Natalija Buza-Vidas, Anne Hultquist, Karina Liuba, Christina Jensen, David Bryder, Liping Yang, Borge Ole-Johan, Lina Thorén, Kristina Anderson, Ewa Sitnicka, Yutaka Sasaki, Mikael Sigvardsson and Sten Eirik Jacobsen. 2005. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment. Cell, vol 121 pp 295-306. Lund University, Medical FacultyRobert Månsson, Anne Hultquist, Sidinh Luc, Liping Yang, Kristina Anderson, Shabnam Kharazi, Suliman Al-Hashmi, Karina Liuba, Lina Thorén, Jörgen Adolfsson, Natalija Buza-Vidas, Hong Qian, Shamit Soneji, Tariq Enver, Mikael Sigvardsson and Sten Eirik Jacobsen. 2007. Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors. Immunity, vol 26 pp 407-419. Lund University, Medical FacultyThe information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012)
- id
- fcd18697-d146-4b30-a77d-c4a74840091b (old id 598830)
- date added to LUP
- 2016-04-01 17:04:22
- date last changed
- 2019-11-19 13:49:08
@phdthesis{fcd18697-d146-4b30-a77d-c4a74840091b, abstract = {{All hematopoietic cells originate from hematopoietic stem cells (HSC) residing in the BM. The process of differentiation, through which HSCs generate progenitors and subsequently mature blood cells has been extensively studied but many of the regulatory mechanisms involved remains elusive. The classical model for hematopoiesis has been established based on the identification of common myeloid precursors and common lymphoid precursors, suggesting that the first lineage commitment step results in the strict separation between the lymphoid and myeloid lineages. However, by subfractionation of the LIN-SCA1+KIT+ bone marrow population, containing all HSCs in the mouse, based on expression of CD34 and FLT3, three functionally distinct populations were identified. CD34- cells contained the HSCs, CD34+FLT3- short term repopulating cells and CD34+ FLT3+/hi cells with combined lymhpoid and GM potential but, only a small fraction (3%) displaying MkE potential in vitro. In agreement with this MkE associated genes (Gata1, Epor, Vwf etc) were found to be down-regulated in CD34+FLT3hi cells while lymphoid associated genes (Il7r, Rag1, Tdt, sterile IgH transcripts) were found to be up-regulated both at the population and single cell level. Based on this we proposed a new model for hematopoietic development were the first restriction point involves the separation of MkE and lymphoid potential while retaining GM potential. In order to investigate the continued development of B-lymphoid cells we investigated the functional role of the transcription factor EBF1, known to be of critical importance for B cell development. By means of comparativ and correlativ analysis of microarray data from cell-lines we, in addition to the previously known EBF1 target genes, identified Vpreb3, CD19, Ceacam1 and CD53 as EBF1 target genes. Furthermore, by transplantations of EBF1 deficient fetal liver cells, we were able to show EBF1 to be dispensable for the generation of CLPs but that lack of EBF1 expression resulted in diminished IgH DJ recombination and reduced expression of B-lineage associated genes already at this early stage of development. Using a hCD25 lambda5-promoter transgene as a marker for EBF1 activity a small CLP subpopulation (~6%) could be identified. This population demonstrated diminished T-cell potential, increased B-cell potential, as well as up-regulation of Vpreb, lambda5, B29, Mb1 and importantly Pax5. Taken together this suggest that B-lineage commitment occurs already at the level of the CLP.}}, author = {{Månsson, Robert}}, isbn = {{978-91-85897-06-3}}, keywords = {{Hematologi; extracellular fluids; Haematology; common lymphoid precursor (CLP); early B-cell factor 1 (EBF1); B-cell; Stemcell; hematopoiesis; extracellulära vätskor; Immunology; serology; transplantation; Immunologi; serologi}}, language = {{eng}}, publisher = {{Lund University: Faculty of Medicine}}, school = {{Lund University}}, title = {{To be or not to be, unraveling molecular mechanisms for lineage decisions in developing blood cells}}, year = {{2007}}, }