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• W1630586606 abstract "textabstractThe adult hematopoietic system is comprised of a hierarchy of cells with the hematopoietic stem cell (HSC) at its foundation. HSCs give rise to progenitors that differentiate into mature hematopoietic cells, which perform the physiological functions of the hematopoietic system. The mature hematopoietic cells have a limited life span and need to be continuously replaced during adult life through the differentiation of HSCs. However, the pool of HSCs also has to be kept intact. The decision whether a dividing HSC differentiates towards a mature hematopoietic cell or preserves it self in an undifferentiated state is a tightly regulated process. An important player in this regulation is the so-called microenvironment (cells surrounding the HSCs). The adult hematopoietic system resides mainly within the bone marrow microenvironment. The hematopoietic supportive microenvironment changes during the development of an organism. Within the embryo the first HSCs are generated in close association with the dorsal aorta (major blood vessel). The dorsal aorta is part of a larger structure referred to as the aorta-gonad-mesonephros (AGM) region. During later stages in development, HSCs are found in the yolk sac, placenta and fetal liver. The fetal liver will eventually harbour the HSCs until birth when they colonize the bone marrow. All these hematopoietic tissues are believed to provide a specialized microenvironment for the generation, expansion and/or maintenance of HSCs. Despite the fact that new insights into the interactions of HSCs and the bone marrow microenvironment have been revealed in the last few years, the interplay between the embryonic microenvironment and the HSCs remains under intensive investigation. To bette! r understand how HSCs communicate with the microenvironments we studied the role of growth factors FGFs and IL-1 and the Runx1 transcription factor in the HSC supportive microenvironments provided by embryonic cell lines and embryos. As an interesting family of growth factors, the Fibroblast Growth Factors (FGFs) have previously been implicated to play a role in the communication between the bone marrow microenvironment and HSCs. As described in chapter 2, our studies showed that FGFs not only influence adult hematopoiesis, but are also regulators of embryonic hematopoiesis. More specifically, FGFs influence the supportive capacities of the AGM microenvironment for hematopoietic progenitors. As it is known that inbred mouse strains differ in HSC pool size as well as cycling activity, we compared the effects of FGFs on the bone marrow supportive microenvironment in six mouse strains. We showed that indeed there are strain-specific hematopoietic cell regulatory differences that could at least be partially due to the FGF signalling pathway. A pro-inflammatory cytokine Interleukin-1 (IL-1) is known to be involved in adult hematopoiesis. In chapter 3 and 4, we show that IL-1 is also an important regulator of progenitors and HSCs in the mouse embryo. In the AGM and fetal liver, IL-1 affects the microenvironment. Strikingly, IL-1 increases both AGM progenitors and HSCs, whereas in fetal liver only progenitor activity is affected. Thus IL-1 acts differentially on HSCs in distinct microenvironments. An important transcription factor in the hematopoietic system is Runx1, which was previously shown to play an intrinsic role in HSCs. Interestingly, Runx1 is also expressed in the cells of the AGM microenvironment. To determine whether Runx1 affects the function of the microenvironment we generated stromal cell lines from AGMs wild type or deficient for Runx1 and studied their supportive capacities for progenitors and HSCs. Our results, as described in chapter 5, show for the first time that the growth of progenitors and HSCs is dependent upon the levels of Runx1 in the AGM microenvironment.The studies presented in this thesis add to our understanding of the role that growth factor, cytokines and transcription factors play in the communication between hematopoietic cells and the microenvironment. The challenge for future research will be to further elucidate the unique vs. overlapping roles of hematopoietic cell regulators in the adult and embryonic microenvironments." @default.
• W1630586606 created "2016-06-24" @default.
• W1630586606 creator A5029290341 @default.
• W1630586606 date "2007-06-27" @default.
• W1630586606 modified "2023-09-27" @default.
• W1630586606 title "The role of the embryonic microenvironment in hematopoietic cell development" @default.
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