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Hypoxia rescues hematopoietic stem cells from oxidative stress-induced cell death and preserves the long-term repopulation ability
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences. (Jan-Ingvar Jönsson)
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences. (Jan-Ingvar Jönsson)
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences. (Jan-Ingvar Jönsson)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A balanced regulation of the ability of hematopoietic stem cells (HSCs) to undergo self-renewal and give rise to new blood cells is crucial for blood homeostasis. Recent studies utilizing genetically modified mice have demonstrated that reactive oxygen species (ROS) damage cellular functions and decrease the lifespan of long-term (LT) HSCs. These LT-HSCs are predominately located in a low-oxygen, or hypoxic, niche, essential for maintaining stem cell capacities. Here, we show that hypoxic culturing rescues HSCs from oxidative stress-induced cell death. Hypoxia inducible factor (HIF)-1 and its target gene pyruvate dehydrogenase kinase 1 (PDK1) were both crucial for survival and long term repopulating ability of HSCs, but less important for hypoxic resistance towards oxidative stress. Moreover, hypoxia increased the expression of Foxo3a, a transcription factor important in adaption to stress stimuli. In conclusion, hypoxia protects LT-HSCs from oxidative stress, possibly by multiple mechanisms, where Foxo3a is likely to play a central role.

Keyword [en]
Hematopoiesis, Stem cells, Progenitor, Hypoxia, Hypoxia-inducible factor 1 alpha, oxidative stress, Puruvate dehydrogenase kinase 1
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-52941OAI: oai:DiVA.org:liu-52941DiVA: diva2:286081
Available from: 2010-01-13 Created: 2010-01-13 Last updated: 2017-01-12
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, PernillaWidegren, EmmaJönsson, Jan-Ingvar

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