Hematopoietic Stem Cell Development and Transcriptional Regulation

The continuous production of blood cells, a process termed hematopoiesis, is sustained throughout the lifetime of an individual by a relatively small population of cells known as hematopoietic stem cells (HSCs). HSCs are unique cells characterized by their ability to self-renew and give rise to all types of mature blood cells. Given their high proliferative potential, HSCs need to be tightly regulated on the cellular and molecular levels or could otherwise turn malignant. On the other hand, the tight regulatory control of HSC function also translates into difficulties in culturing and expanding HSCs in vitro. In fact, it is currently not possible to maintain or expand HSCs ex vivo without rapid loss of self-renewal. Increased knowledge of the unique features of important HSC niches and of key transcriptional regulatory programs that govern HSC behavior is thus needed. Additional insight in the mechanisms of stem cell formation could enable us to recapitulate the processes of HSC formation and self-renewal/expansion ex vivo with the ultimate goal of creating an unlimited supply of HSCs from e.g. human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPS) to be used in therapy. We thus asked: How are hematopoietic stem cells formed and in what cellular niches does this happen (Papers I, II)? What are the molecular mechanisms that govern hematopoietic stem cell development and differentiation (Papers III, IV)? Importantly, we could show that placenta is a major fetal hematopoietic niche that harbors a large number of HSCs during midgestation (Paper I)(Gekas et al., 2005). In order to address whether the HSCs found in placenta were formed there we utilized the Runx1-LacZ knock-in and Ncx1 knockout mouse models (Paper II). Importantly, we could show that HSCs emerge de novo in the placental vasculature in the absence of circulation (Rhodes et al., 2008). Furthermore, we could identify defined microenvironmental niches within the placenta with distinct roles in hematopoiesis: the large vessels of the chorioallantoic mesenchyme serve as sites of HSC generation whereas the placental labyrinth is a niche supporting HSC expansion (Rhodes et al., 2008). Overall, these studies illustrate the importance of distinct milieus in the emergence and subsequent maturation of HSCs. To ensure proper function of HSCs several regulatory mechanisms are in place. The microenvironment in which HSCs reside provides soluble factors and cell-cell interactions. In the cell-nucleus, these cell-extrinsic cues are interpreted in the context of cell-intrinsic developmental programs which are governed by transcription factors. An essential transcription factor for initiation of hematopoiesis is Scl/Tal1 (stem cell leukemia gene/T-cell acute leukemia gene 1). Loss of Scl results in early embryonic death and total lack of all blood cells, yet deactivation of Scl in the adult does not affect HSC function (Mikkola et al., 2003b. In order to define the temporal window of Scl requirement during fetal hematopoietic development, we deactivated Scl in all hematopoietic lineages shortly after hematopoietic specification in the embryo . Interestingly, maturation, expansion and function of fetal HSCs was unaffected, and, as in the adult, red blood cell and platelet differentiation was impaired (Paper III)(Schlaeger et al., 2005). These findings highlight that, once specified, the hematopoietic fate is stable even in the absence of Scl and is maintained through mechanisms that are distinct from those required for the initial fate choice. As the critical downstream targets of Scl remain unknown, we sought to identify and characterize target genes of Scl (Paper IV). We could identify transcription factor Mef2C (myocyte enhancer factor 2 C) as a novel direct target gene of Scl specifically in the megakaryocyte lineage which largely explains the megakaryocyte defect observed in Scl deficient mice. In addition, we observed an Scl-independent requirement of Mef2C in the B-cell compartment, as loss of Mef2C leads to accelerated B-cell aging (Gekas et al. Submitted). Taken together, these studies identify key extracellular microenvironments and intracellular transcriptional regulators that dictate different stages of HSC development, from emergence to lineage choice to aging.

Bridging East and West : The Establishment of the International Institute for Applied Systems Analysis (IIASA) in the United States Foreign Policy of Bridge Building, 1964-1972.

The dissertation examines the foreign policies of the United States through the prism of science and technology. In the focal point of scrutiny is the policy establishing the International Institute for Applied Systems Analysis (IIASA) and the development of the multilateral part of bridge building in American foreign policy during the 1960s and early 1970s. After a long and arduous negotiation process, the institute was finally established by twelve national member organizations from the following countries: Bulgaria, Canada, Czechoslovakia, Federal Republic of Germany (FRG), France, German Democratic Republic (GDR), Great Britain, Italy, Japan, Poland, Soviet Union and United States; a few years later Sweden, Finland and the Netherlands also joined. It is said that the goal of the institute was to bring together researchers from East and West to solve pertinent problems caused by the modernization process experienced in industrialized world. It originates from President Lyndon B. Johnson s bridge building policies that were launched in 1964, and was set in a well-contested and crowded domain of other international organizations of environmental and social planning. Since the distinct need for yet another organization was not evident, the process of negotiations in this multinational environment enlightens the foreign policy ambitions of the United States on the road to the Cold War détente. The study places this project within its political era, and juxtaposes it with other international organizations, especially that of the OECD, ECE and NATO. Conventionally, Lyndon Johnson s bridge building policies have been seen as a means to normalize its international relations bilaterally with different East European countries, and the multilateral dimension of the policy has been ignored. This is why IIASA s establishment process in this multilateral environment brings forth new information on US foreign policy goals, the means to achieve these goals, as well as its relations to other advanced industrialized societies before the time of détente, during the 1960s and early 1970s. Furthermore, the substance of the institute applied systems analysis illuminates the differences between European and American methodological thinking in social planning. Systems analysis is closely associated with (American) science and technology policies of the 1960s, especially in its military administrative applications, thus analysis within the foreign policy environment of the United States proved particularly fruitful. In the 1960s the institutional structures of European continent with faltering, and the growing tendencies of integration were in flux. One example of this was the long, drawn-out process of British membership in the EEC, another is de Gaulle s withdrawal from NATO s military-political cooperation. On the other hand, however, economic cooperation in Europe between East and West, and especially with the Soviet Union was expanding rapidly. This American initiative to form a new institutional actor has to be seen in that structural context, showing that bridge building was needed not only to the East, but also to the West. The narrative amounts to an analysis of how the United States managed both cooperation and conflict in its hegemonic aspirations in the emerging modern world, and how it used its special relationship with the United Kingdom to achieve its goals. The research is based on the archives of the United States, Great Britain, Sweden, Finland, and IIASA. The primary sources have been complemented with both contemporary and present day research literature, periodicals, and interviews.

När finanskrisen slog till i Finland

Avhandlingen kartlägger användandet av metaforer i ekonomijournalistik då den globala ekonomikrisen anlände till Finland under hösten 2008. Syftet med den här kvalitativa forskningen är inte bara att presentera olika metaforer utan också påvisa att metaforer bildar större helheter. Med hjälp av en metaforanalys redogör denna studie vilka metaforer förekom i ekonominyheter och hur de reflekterar ekonomikrisen och den verklighet vi lever i. Forskningen presenterar också deltagarna i ekonomikrisdiskussionen och diskuterar deras position i samhället i förhållande till maktfrågan. Den tredelning av metaforer som Lakoff och Johnson presenterar i sin bok Metaphors we live by (1980) ligger till grund för den här undersökningen. I den här forskningen delas metaforer enligt den kognitiva metaforteorin till tre större grupper; strukturella, ontologiska och orientationella metaforer. Användning av metaforer i undersökta artiklar var rikligt och den största gruppen utgjordes av strukturella metaforer. Mest förekom krigs-, spel-, sjukdoms- och naturmetaforer. Den största gruppen var krigsmetaforer vilka tillsammans med spelmetaforer användes mest i början av rapporteringen om den ekonomiska recessionen. Färg- och religionsmetaforer förekom också om än i ett mindre antal. Ontologiska metaforer förekom i form av personifiering. Bland annat var marknad och börs de fenomen som fick personliga drag då de var i panik, reagerade föll eller sov. Av de orientationella metaforer var horisontella upp-ner -metaforer vanligare än de vertikala fram-bak -metaforerna. Denna studie visar att de metaforer som journalisterna använde i sina artiklar bildade större helheter. Med hjälp av dessa metaforer ville man förtydliga att den ekonomiska recessionen ansågs vara en överraskning, speciellt för makthavare och ekonomiexperter. Krisen slog till i Finland överraskande och med en mycket stark volym och osäkerheten om framtiden förstärktes med metaforanvändandet. Avhandlingen har också ett samhälleligt perspektiv. I den undersöks deltagarna i ekonomikrisdiskussionen samt deras position i samhället. Forskningsresultatet är relaterat till maktfrågan med stöd av maktforskarna Michel Foucault och Ilkka Ruostetsaari. I dagens samhälle och globala värld har ekonomins makt bara ökat. Analysen av det empiriska materialet visar att näringslivet dominerade debatten och därmed hör det till makteliten. Alla diskussionsdeltagare använder metaforer, dock används de kraftigaste metaforerna av journalister.