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Hematopoietic stem cells: c-mpl and TNF receptor function

Ramsfjell, Veslemøy LU (1999)
Abstract
Hematopoietic stem cells (HSC) are crucial to life. Daily and throughout the life span of an individual they are responsible for replacing approximately 10(12) mature blood cells. Mature cells are, for example, required for transportation of oxygen, defense against infections and to stop bleeding. Thus, our aim with this study was to characterize these rare murine (Lin-Sca1+c-kit+) and human (CD34+CD38-) bone marrow (BM) HSC with respect to their viability, proliferation, differentiation and expansion in response to cytokines. When these studies were initiated thrombopoietin (Tpo) was postulated to act primarily as a megakaryocyte lineage-specific factor. However, we demonstrated that Tpo directly and synergistically enhanced multilineage... (More)
Hematopoietic stem cells (HSC) are crucial to life. Daily and throughout the life span of an individual they are responsible for replacing approximately 10(12) mature blood cells. Mature cells are, for example, required for transportation of oxygen, defense against infections and to stop bleeding. Thus, our aim with this study was to characterize these rare murine (Lin-Sca1+c-kit+) and human (CD34+CD38-) bone marrow (BM) HSC with respect to their viability, proliferation, differentiation and expansion in response to cytokines. When these studies were initiated thrombopoietin (Tpo) was postulated to act primarily as a megakaryocyte lineage-specific factor. However, we demonstrated that Tpo directly and synergistically enhanced multilineage growth and differentiation from both Lin-Sca1+c-kit+ and CD34+CD38- BM cells, when combined with cytokines like c-kit ligand (KL), flt3 ligand (FL), and the interleukins 3 and 11. In addition, Tpo, more than any other early-acting cytokines, efficiently promoted viability of single CD34+CD38- cells in the absence of cell division, further implicating that Tpo directly acted on candidate stem cells. Interestingly, a direct comparison of human long-term culture-initiating cells (LTC-IC) and the more primitive extended LTC-IC (ELTC-IC), demonstrated distinct and stringent requirements for their ex vivo expansion. Specifically, ELTC-IC were potently expanded in serum-free medium in the presence of high concentrations of KL+FL+Tpo for 12 days. We also observed that Tpo-induced clonal growth of human CD34+CD38- progenitor cells was almost completely abrogated by tumor necrosis factor-a (TNF-a) and transforming growth factor-b. Additionally, we demonstrated in mice that functional signaling through the Fas and TNF receptors severely compromised HSC short- and long-term multilineage repopulating activity. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Dr Ploemacher, R., Erasmus University, Rotterdam, The Netherlands
organization
publishing date
type
Thesis
publication status
published
subject
keywords
tumor necrosis factor-a., in vivo reconstitution, ex vivo expansion, long-term bone marrow culture, differentiation, proliferation, synergy, Hematopoietic stem cells, thrombopoietin, Haematology, extracellular fluids, Hematologi, extracellulära vätskor
pages
141 pages
defense location
WNC, Sölvegatan 17, Lund
defense date
1999-11-03 10:15
external identifiers
  • Other:ISRN: LUMEDW/MEMT--1002-SE
ISBN
91-628-3669-2
language
English
LU publication?
yes
id
ad75a75e-9bb3-4569-a765-0eb312ff4304 (old id 39800)
date added to LUP
2007-07-31 14:05:28
date last changed
2016-09-19 08:45:17
@misc{ad75a75e-9bb3-4569-a765-0eb312ff4304,
  abstract     = {Hematopoietic stem cells (HSC) are crucial to life. Daily and throughout the life span of an individual they are responsible for replacing approximately 10(12) mature blood cells. Mature cells are, for example, required for transportation of oxygen, defense against infections and to stop bleeding. Thus, our aim with this study was to characterize these rare murine (Lin-Sca1+c-kit+) and human (CD34+CD38-) bone marrow (BM) HSC with respect to their viability, proliferation, differentiation and expansion in response to cytokines. When these studies were initiated thrombopoietin (Tpo) was postulated to act primarily as a megakaryocyte lineage-specific factor. However, we demonstrated that Tpo directly and synergistically enhanced multilineage growth and differentiation from both Lin-Sca1+c-kit+ and CD34+CD38- BM cells, when combined with cytokines like c-kit ligand (KL), flt3 ligand (FL), and the interleukins 3 and 11. In addition, Tpo, more than any other early-acting cytokines, efficiently promoted viability of single CD34+CD38- cells in the absence of cell division, further implicating that Tpo directly acted on candidate stem cells. Interestingly, a direct comparison of human long-term culture-initiating cells (LTC-IC) and the more primitive extended LTC-IC (ELTC-IC), demonstrated distinct and stringent requirements for their ex vivo expansion. Specifically, ELTC-IC were potently expanded in serum-free medium in the presence of high concentrations of KL+FL+Tpo for 12 days. We also observed that Tpo-induced clonal growth of human CD34+CD38- progenitor cells was almost completely abrogated by tumor necrosis factor-a (TNF-a) and transforming growth factor-b. Additionally, we demonstrated in mice that functional signaling through the Fas and TNF receptors severely compromised HSC short- and long-term multilineage repopulating activity.},
  author       = {Ramsfjell, Veslemøy},
  isbn         = {91-628-3669-2},
  keyword      = {tumor necrosis factor-a.,in vivo reconstitution,ex vivo expansion,long-term bone marrow culture,differentiation,proliferation,synergy,Hematopoietic stem cells,thrombopoietin,Haematology,extracellular fluids,Hematologi,extracellulära vätskor},
  language     = {eng},
  pages        = {141},
  title        = {Hematopoietic stem cells: c-mpl and TNF receptor function},
  year         = {1999},
}