Signal Balance as a Pluripotency Determinant: In vitro modeling of in vivo pluripotency states with WNT, FGF and BMP

This thesis enriches the body of knowledge around pluripotency by describing a novel pluripotent state. It deepens our understanding of cell biology, the processes establishing pluripotency and provides new insights into improving the process of artificial generation of pluripotent cells

Tailoring the A and B site of Fe-based perovskites for high selectivity in the reverse water-gas shift reaction

The reverse water-gas shift reaction (rWGS) is of particular interest as it is the first step to producing high-added-value products from carbon dioxide (CO2) and renewable hydrogen (H2), such as synthetic fuels or other chemical building blocks (e.g. methanol) through a modified Fischer-Tropsch process. However, side reactions and material deactivation issues, depending on the conditions used, still make it challenging. Efforts have been put into developing and improving scalable catalysts that can deliver high selectivity while at the same time being able to avoid deactivation through high temperature sintering and/or carbon deposition. Here we design a set of perovskite ferrites specifically tailored to the hydrogenation of CO2 via the reverse water-gas shift reaction. We tailor the oxygen vacancies, proven to play a major role in the process, by partially substituting the primary A-site element (Barium, Ba) with Praseodymium (Pr) and Samarium (Sm), and also dope the B-site with a small amount of Nickel (Ni). We also take advantage of the exsolution process and manage to produce highly selective Fe-Ni alloys that suppress the formation of any by-products, leading to up to 100% CO selectivity

Endogenous WNT signals mediate BMP-induced and spontaneous differentiation of epiblast stem cells and human embryonic stem cells

Therapeutic application of human embryonic stem cells (hESCs) requires precise control over their differentiation. However, spontaneous differentiation is prevalent, and growth factors induce multiple cell types; e.g., the mesoderm inducer BMP4 generates both mesoderm and trophoblast. Here we identify endogenous WNT signals as BMP targets that are required and sufficient for mesoderm induction, while trophoblast induction is WNT independent, enabling the exclusive differentiation toward either lineage. Furthermore, endogenous WNT signals induce loss of pluripotency in hESCs and their murine counterparts, epiblast stem cells (EpiSCs). WNT inhibition obviates the need to manually remove differentiated cells to maintain cultures and improves the efficiency of directed differentiation. In EpiSCs, WNT inhibition stabilizes a pregastrula epiblast state with novel characteristics, including the ability to contribute to blastocyst chimeras. Our findings show that endogenous WNT signals function as hidden mediators of growth factor-induced differentiation and play critical roles in the self-renewal of hESCs and EpiSCs

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Endogenous WNT Signals Mediate BMP-Induced and Spontaneous Differentiation of Epiblast Stem Cells and Human Embryonic Stem Cells

Summary: Therapeutic application of human embryonic stem cells (hESCs) requires precise control over their differentiation. However, spontaneous differentiation is prevalent, and growth factors induce multiple cell types; e.g., the mesoderm inducer BMP4 generates both mesoderm and trophoblast. Here we identify endogenous WNT signals as BMP targets that are required and sufficient for mesoderm induction, while trophoblast induction is WNT independent, enabling the exclusive differentiation toward either lineage. Furthermore, endogenous WNT signals induce loss of pluripotency in hESCs and their murine counterparts, epiblast stem cells (EpiSCs). WNT inhibition obviates the need to manually remove differentiated cells to maintain cultures and improves the efficiency of directed differentiation. In EpiSCs, WNT inhibition stabilizes a pregastrula epiblast state with novel characteristics, including the ability to contribute to blastocyst chimeras. Our findings show that endogenous WNT signals function as hidden mediators of growth factor-induced differentiation and play critical roles in the self-renewal of hESCs and EpiSCs. : ten Berge and colleagues show that BMP signals direct the differentiation of human and mouse pluripotent cells via the induction of endogenous WNT signals. These determine trophoblast or primitive streak lineage specification. Furthermore, inhibition of endogenous WNT signals prevents spontaneous differentiation in both hESCs and mouse epiblast stem cells (EpiSCs) and maintains EpiSCs in a pregastrula, chimera-competent state

BMP and Hedgehog Regulate Distinct AGM Hematopoietic Stem Cells Ex Vivo

Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy, are generated during embryonic stages. The first HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through endothelial to a hematopoietic transition. BMP4 and Hedgehog affect their production and expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smad-activated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type is BMP-activated and the other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signaling through the VEGF pathway. Transcriptomic analyses demonstrate that the two HSC types express distinct but overlapping genetic programs. These results revealing the bifurcation in HSC types at early embryonic stages in the AGM explant model suggest that their development is dependent upon the signaling molecules in the microenvironment