THE HYPOXIC HEMATOPOIETIC STEM CELL NICHE Consequences of Hypoxia-induced Transcription on Stem Cell Fate

Hematopoiesis is the process of blood formation that originates with the hematopoietic stem cell (HSC), a cell type that is responsible for the life-long supply of mature blood cells. HSCs are defined by their ability to self-renew as well as giving rise to differentiated cells of all blood lineages. Because of these features, HSCs are also the basis for bone marrow transplantation regimens for treatment of leukemia and various other hematopoietic disorders. HSCs reside in the bone marrow of adult mammals, in the so called niche. The HSC niche refers to the specific anatomical region where the stem cells reside, but also to the regulatory microenvironment consisting of adjacent cells and factors produced by these. An important feature of the HSC niche seems to be a relatively low level of oxygen: hypoxia. Hypoxia leads to activation of Hypoxia-Inducible Factors (HIF). We have investigated the role of hypoxia and HIFs in HSC biology. By in vitro hypoxic treatment, we could show that hypoxia leads to less proliferation of HSCs, with up-regulation of cell-cycle inhibitory genes, while full reconstitution potential of irradiated recipient mice is preserved. Ectopic activation of HIF, mediated by retroviral overexpression in hematopoietic stem and progenitor cells (HSPC), leads to even less proliferation and a disability to sustain hematopoiesis in vivo. The role of the HIF target gene Vegfa was studied in a mouse model where hypoxia-induced transcription of Vegfa is abrogated (Vegfaδ/δ). HSCs could be maintained under steady-state conditions without hypoxic induction of Vegfa. In transplantation assays however, we show that when Vegfa upregulation upon hypoxia is lacking, adult HSC function is clearly impaired. On the contrary, HSCs isolated from the fetal liver of developing Vegfaδ/δ mice had a normal function. Furthermore, we show that erythropoiesis during development and to a lesser extent in the adult involves hypoxic Vegfa expression. In summary, this thesis contributes new findings to the role of the hypoxic HSC niche. We show that hypoxia and HIFs are involved in regulating HSC proliferation. Furthermore, hypoxia-induced Vegfa is identified as an important player in HSCs

HIF-1α can act as a tumor suppressor gene in murine Acute Myeloid Leukemia.

Self-renewal of hematopoietic stem cells (HSCs) and leukemia-initiating cells (LICs) has been proposed to be influenced by low oxygen tension (hypoxia). This signaling, related to the cellular localization inside the bone marrow niche and/or influenced by extrinsic factors, promotes the stabilization of hypoxia inducible factors (HIFs). Whether HIF-1α can be used as a therapeutic target in the treatment of myeloid malignancies remains unknown. We have used three different murine models to investigate the role of HIF-1α in acute myeloid leukemia (AML) initiation/progression and self-renewal of LICs. Unexpectedly, we failed to observe a delay or prevention of disease development from hematopoietic cells lacking Hif-1α. In contrast, deletion of Hif-1α resulted in faster development of the disease and an enhanced leukemia phenotype in some of the investigated models. Our results therefore warrant a reconsideration of the role of HIF-1α and, as a consequence, question its generic therapeutic usefulness in AML

Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche.

Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or upregulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfa(δ/δ), where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfa(δ/δ) mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-Vegfa axis

The Effect of Work-Family Reconciliation Policies on First-Birth Childbearing Intentions in Poland and Sweden

Many countries in Europe have experienced fertility below replacement level for a long period of time. Population ageing and difficulties in sustaining current living standards follow low fertility levels. To be able to increase fertility levels it is necessary to give women and men in Europe opportunities to fulfil their desired life, with or without children. Work-family reconciliation policies can either prevent people from or allow them to combine a career and a family. To what extent these policies have an influence on short-term childbearing intentions in Poland and Sweden is the focus of this study. Using data from the Gender and Generation Survey, the results show that women in Poland are more likely to intend to have a first child within the next three years than are women in Sweden, despite less favourable work-family reconciliation policies, while childless men in Poland are less likely to intend to have a child in the near future than are men in Sweden. It also shows that the attitudes towards parental leave policies have an effect on first childbearing intentions, but that attitudes towards childcare systems play a minor role when intending to become a parent or not in the near future. Common to the work-family reconciliation policies is that the attitudes towards them are contextually embedded

”Sometimes I feel so invisible I wonder if I’m here at all.” : - en analys av existentiella teman i filmen Där kräftorna sjunger

The purpose of this study is to identify the existential themes present in the movie Where the crawdads sing (2022) by using the method thematic content analysis. The method is used when the aim is to identify themes or patterns within the data. In the movie the main character, Kya, faces challenges in life that raise existential thoughts and questions that together point to the existential themes being identified. Furthermore, the study examined how the main character deals with these existential challenges by applying Pargament’s religious coping theory. The theory explains how people use religious or spiritual beliefs to cope with stress and adversity. The research questions for this study are:  What existential themes challenge Kya? How does Kya relate and deal with these existential challenges? The result of the study showed that the movie explores themes of social context, to be exposed to threats and thoughts of life and death. When researching how Kya copes with her challenges, it was discovered that nature and social relationships are significant for Kya throughout the movie. However, she uses a reconstructive coping mechanism in order to conserve her significance. Kya does this by getting rid of obstacles in her way.

”Sometimes I feel so invisible I wonder if I’m here at all.” : - en analys av existentiella teman i filmen Där kräftorna sjunger

The purpose of this study is to identify the existential themes present in the movie Where the crawdads sing (2022) by using the method thematic content analysis. The method is used when the aim is to identify themes or patterns within the data. In the movie the main character, Kya, faces challenges in life that raise existential thoughts and questions that together point to the existential themes being identified. Furthermore, the study examined how the main character deals with these existential challenges by applying Pargament’s religious coping theory. The theory explains how people use religious or spiritual beliefs to cope with stress and adversity. The research questions for this study are:  What existential themes challenge Kya? How does Kya relate and deal with these existential challenges? The result of the study showed that the movie explores themes of social context, to be exposed to threats and thoughts of life and death. When researching how Kya copes with her challenges, it was discovered that nature and social relationships are significant for Kya throughout the movie. However, she uses a reconstructive coping mechanism in order to conserve her significance. Kya does this by getting rid of obstacles in her way.

(H)if blood stem cells gO 2 sleep: What can wake them up?

Comment on: Rehn M, et al. Blood 2011; 118:1534-43