HSCS AND HIF

The role of hypoxia-inducible factors in human haematopoietic stem cell biology and leukaemogenesis

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 Obiettivo del progetto (Objective)

'Mammalian haematopoiesis in the adult takes place predominantly in the bone marrow (BM) where a population of haematopoietic stem cells (HSC) are located. HSC are able to self-renew and give rise to all the blood cell types. The fate choice of HSC to either self-renew or differentiate is controlled by an interplay between intrinsic mechanisms and extrinsic signals from the surrounding environment called stem cell niche. The existence of a hypoxic niche in the BM has been highlighted in the last decade. It has been proposed that the most quiescent HSC reside in the most hypoxic areas in the BM suggesting that low oxygen levels might play a key role in the maintenance of HSC. However the molecular mechanisms by which HSC respond to hypoxia have not been elucidated. Cells have developed a molecular mechanism for oxygen sensing. An important mediator is the transcriptional complex hypoxia-inducible factor (HIF). At low oxygen levels, HIF is stabilized and regulates the transcription of crucial genes involved in cell proliferation, survival and differentiation. Under normoxia, HIF has a low transcriptional activity. In addition, HIF has been reported to be upregulated in certain pathological conditions such as cancer where a high expression of HIF correlates with a poor prognosis. The aim of this project is to understand the molecular mechanisms by which human HSC response to their hypoxic environment. I will address this question by studying the role of HIF in HSC. I will first concentrate on analysing the consequences that genetically manipulating HIF might have on HSC in vitro and in vivo. Secondly I will analyse whether HIF is upregulated in leukemic stem cells (LSC) and in such a case, I will finally investigate the consequences that downregulating HIF might have in the modulation of leukaemia. Defining the role of HIF in HSC and LSC will provide for the first time a molecular link between the hypoxic niche, HSC maintenance and leukaemia development in humans.'

Introduzione (Teaser)

Blood homeostasis is maintained by a small population of cells that reside in the bone marrow and are known as haematopoietic stem cells (HSCs). Understanding the conditions required for the maintenance and function of these cells could have important implications for both health and disease.

Descrizione progetto (Article)

Like other tissue-specific stem cells, HSCs have the capacity to self-renew or differentiate into different blood cell types. Central to this decision is the bone marrow microenvironment and the cues it provides.

Accumulating evidence indicates that HSCs are exposed to low oxygen levels in the bone marrow but the underlying molecular mechanisms have not been elucidated. With this in mind, scientists on the EU-funded 'The role of hypoxia-inducible factors in human haematopoietic stem cell biology and leukaemogenesis' (HSCS AND HIF) project decided to investigate the hypoxia-sensing system known as hypoxia inducible factor (HIF).

Under normal oxygen levels, HIF has low transcriptional activity. However, at low oxygen levels, HIF regulates the transcription of crucial genes involved in cell proliferation, survival and differentiation. High HIF levels have also been reportedly found in various types of cancer and are associated with poor prognosis.

Scientists looked at the levels of HIF factors in human HSCs and demonstrated their necessity for successful transplantation in a mouse model. Importantly, HIF2 affects the self-renewal of HSCs and their ability to maintain their stem-cell phenotype.

Gene expression analysis of HSCs with reduced HIF levels underscored its importance in mitochondria homeostasis and reactive oxygen species production. Knockdown of HIF did not only make normal HSCs more prone to apoptosis but also impeded the growth of leukaemia cells.

Collectively, the results of the HSCS AND HIF study provided the molecular link between the HSC phenotype and the hypoxic niche. The generated observations could have significant consequences for normal bone marrow transplantation. Results also offer a cue on how leukaemic cells evade chemotherapy and radiation.