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Hypoxia Expands Primitive Hematopoietic Progenitor Cells from Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Lund University.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
2006 (English)In: Journal of Stem Cells, Vol. 1, no 4, 247-257 p.Article in journal (Refereed) Published
Abstract [en]

Self-renewal is a prerequisite for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow throughout adult life. Cytokines are mainly providing pro-survival signals of HSC, whereas low oxygen levels (hypoxia) were recently shown to influence self-renewal. In contrast, the effects on other progenitor cell types is not clear. In the present work, we have analyzed whether hypoxia has any effects on mouse multipotent progenitors. When bone marrow-derived Lin-Sca1+c-kit+ (LSK) cells were kept in hypoxic cultures (1% O2 ) for 4 days together with cytokines, the numbers of colony forming high-proliferative progenitors (HPP-CFC) and precursors for cobble-stone forming cells (CAFC) were increased compared to normoxic conditions. A similar effect was seen with pre-CFCmulti from unfractionated bone marrow, whereas more committed progenitors (CFU-GM) were expanded better in normoxia compared to hypoxia. The observed increase in numbers of primitive colony-forming progenitor cells was associated with maintenance of the c-kit/Sca-1 phenotype and a preferential expansion of immature  blast-like appearing cells. The results suggest that a major function of hypoxia is to regulate differentiation by increased self-renewal. Furthermore, in cultures of limited cytokine supply, survival of the stem cell-like cell line FDCP-mix was increased during hypoxia. Thus, hypoxia allows for better survival and self-renewal of multipotent progenitors and HSCs from adult bone marrow. Such culture conditions may have beneficial clinical implications for ex vivo purposes and may improve the yields of stem cells and early progenitors.

Place, publisher, year, edition, pages
2006. Vol. 1, no 4, 247-257 p.
Keyword [en]
Hematopoiesis, Stem cells, Progenitor, Hypoxia, Survival, Self-renewal
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-17713OAI: oai:DiVA.org:liu-17713DiVA: diva2:211532
Note
Original Publication: Pernilla Eliasson, Richard Karlsson and Jan-Ingvar Jönsson, Hypoxia Expands Primitive Hematopoietic Progenitor Cellsfrom Mouse Bone Marrow During In Vitro Culture and Preserves the Colony-Forming Ability, 2006, Journal of Stem Cells, (1), 4, 247-257. https://www.novapublishers.com/catalog/editorial.php?products_id=3730 Copyright: Nova Science Publishers https://www.novapublishers.com/ Available from: 2009-04-16 Created: 2009-04-16 Last updated: 2017-01-12Bibliographically approved
In thesis
1. Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
Open this publication in new window or tab >>Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 93 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1160
Keyword
hematopoietic stem cells, hypoxia, self-renewal, survival, acute myeloid leukemia, FLT3
National Category
Biochemistry and Molecular Biology Hematology
Identifiers
urn:nbn:se:liu:diva-52932 (URN)978-91-7393-470-1 (ISBN)
Public defence
2009-12-11, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Note

On the day of the defence date the title of article II was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.

Available from: 2010-01-19 Created: 2010-01-13 Last updated: 2017-01-12Bibliographically approved

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Eliasson, Pernilla Jönsson, Jan-Ingvar

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