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Cytokine Regulation of Hematopoietic Stem Cells and Lymphopoiesis

Buza-Vidas, Natalija LU (2007) In 2007:15
Abstract
Large numbers of blood cells need to be continuously replaced in order to sustain the crucial functions of the immune system, oxygen transport and blood clotting. The large diversity of cell types required to maintain the integrity of the blood system are all produced from blood forming or hematopoietic stem cells (HSCs). HSCs have the unique property of self renewal, ensuring life-long replenishment of all the blood cell types. Hematopoietic growth factors, so called cytokines, have previously been demonstrated to be important for the survival and proliferation of committed progenitor cells and development of different blood cell lineages. However, their potential role in regulating HSCs remains to a large degree unresolved. Herein, we... (More)
Large numbers of blood cells need to be continuously replaced in order to sustain the crucial functions of the immune system, oxygen transport and blood clotting. The large diversity of cell types required to maintain the integrity of the blood system are all produced from blood forming or hematopoietic stem cells (HSCs). HSCs have the unique property of self renewal, ensuring life-long replenishment of all the blood cell types. Hematopoietic growth factors, so called cytokines, have previously been demonstrated to be important for the survival and proliferation of committed progenitor cells and development of different blood cell lineages. However, their potential role in regulating HSCs remains to a large degree unresolved. Herein, we provide data that establish the adaptor protein LNK as an important negative regulator of postnatal HSC expansion, acting as an inhibitor of the cytokine Thrombopoietin, known to be important for HSC maintenance and/or expansion. Furthermore, whereas previous studies demonstrated that another cytokine, fms-like tyrosine kinase receptor 3 (FLT3) ligand (FL), is an important regulator of B cell progenitors but has a redundant role in steady state maintenance of mature B cells, we here demonstrate that FL plays a crucial role in the regeneration of not only B cell progenitors but also mature B cells after bone marrow (BM) transplantation and chemotherapy. In addition, through studies of FL-deficient mice we show that FL plays an important role in maintaining conventional B cells with age, but is redundant in maintaining a normal compartment of fetally/postnatally derived B1 and marginal zone B cells. It has been disputed whether FL also is important in HSC regulation. Our present findings establish that FL is not important for regulating HSC maintenance or expansion neither during fetal development or in adult steady state hematopoiesis, nor following BM transplantation or chemotherapy-induced BM ablation. Finally, through identification of a multipotent progenitor in adult BM, with sustained granulocyte-monocyte and lymphocyte potential, but little or no megakaryocyte and erythroid potential, we provide evidence for a strict separation of myelopoiesis and lymphopoiesis, not being the first lineage commitment step of HSCs. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Ph.D. Georgopoulos, Katia, Harvard Medical School
organization
publishing date
type
Thesis
publication status
published
subject
keywords
extracellular fluids, Hematologi, Haematology, Medicin (människa och djur), Medicine (human and vertebrates), lineage commitment, cytokines, lymphopoiesis, extracellulära vätskor, transplantation, hematopoietic stem cells
in
2007:15
pages
200 pages
publisher
Hematopoietic Stem Cell Laboratory
defense location
Conference room D1539, BMC, Klinikgatan 32, Lund
defense date
2007-03-17 10:00
ISSN
1652-8220
ISBN
91-85559-66-0
language
English
LU publication?
yes
id
ccaf51c9-3f44-4e39-a7c0-d5defbcbcc90 (old id 548230)
date added to LUP
2007-09-10 12:41:57
date last changed
2016-09-19 08:44:55
@phdthesis{ccaf51c9-3f44-4e39-a7c0-d5defbcbcc90,
  abstract     = {Large numbers of blood cells need to be continuously replaced in order to sustain the crucial functions of the immune system, oxygen transport and blood clotting. The large diversity of cell types required to maintain the integrity of the blood system are all produced from blood forming or hematopoietic stem cells (HSCs). HSCs have the unique property of self renewal, ensuring life-long replenishment of all the blood cell types. Hematopoietic growth factors, so called cytokines, have previously been demonstrated to be important for the survival and proliferation of committed progenitor cells and development of different blood cell lineages. However, their potential role in regulating HSCs remains to a large degree unresolved. Herein, we provide data that establish the adaptor protein LNK as an important negative regulator of postnatal HSC expansion, acting as an inhibitor of the cytokine Thrombopoietin, known to be important for HSC maintenance and/or expansion. Furthermore, whereas previous studies demonstrated that another cytokine, fms-like tyrosine kinase receptor 3 (FLT3) ligand (FL), is an important regulator of B cell progenitors but has a redundant role in steady state maintenance of mature B cells, we here demonstrate that FL plays a crucial role in the regeneration of not only B cell progenitors but also mature B cells after bone marrow (BM) transplantation and chemotherapy. In addition, through studies of FL-deficient mice we show that FL plays an important role in maintaining conventional B cells with age, but is redundant in maintaining a normal compartment of fetally/postnatally derived B1 and marginal zone B cells. It has been disputed whether FL also is important in HSC regulation. Our present findings establish that FL is not important for regulating HSC maintenance or expansion neither during fetal development or in adult steady state hematopoiesis, nor following BM transplantation or chemotherapy-induced BM ablation. Finally, through identification of a multipotent progenitor in adult BM, with sustained granulocyte-monocyte and lymphocyte potential, but little or no megakaryocyte and erythroid potential, we provide evidence for a strict separation of myelopoiesis and lymphopoiesis, not being the first lineage commitment step of HSCs.},
  author       = {Buza-Vidas, Natalija},
  isbn         = {91-85559-66-0},
  issn         = {1652-8220},
  keyword      = {extracellular fluids,Hematologi,Haematology,Medicin (människa och djur),Medicine (human and vertebrates),lineage commitment,cytokines,lymphopoiesis,extracellulära vätskor,transplantation,hematopoietic stem cells},
  language     = {eng},
  pages        = {200},
  publisher    = {Hematopoietic Stem Cell Laboratory},
  school       = {Lund University},
  series       = {2007:15},
  title        = {Cytokine Regulation of Hematopoietic Stem Cells and Lymphopoiesis},
  year         = {2007},
}