Retrospective analysis of mesendoderm progenitors that give rise to cardiac microtissues, multilineage and gut organoids
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ABSTRACT:
PROVIDER: PRJNA641388 | ENA |
REPOSITORIES: ENA
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Project description:Bulk RNA-sequencing of the mesendoderm progenitors before aggregation. Mesendoderm progenitors aggregates can lead to the formation of cardiac microtissues, multilineage and gut organoids in different batches. Despite batch-to-batch differences in spheroid phenotype, all spheroids (n>200) within a single batch derived from the same initial differentiation of progenitor cells manifested identical morphologies and cellularity.
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Project description:Self-renewing tissue-resident macrophages are thought to be exclusively derived from embryonic progenitors. However, whether circulating monocytes can also give rise to such macrophages has not been formally investigated. Here we use a new model of diphtheria toxin-mediated depletion of liver-resident Kupffer cells to generate niche availability and show that circulating monocytes engrafted in the liver, gradually adopt the transcriptional profile of their depleted counterparts and become long-lived self-renewing cells. Underlining the physiological relevance of our findings, circulating monocytes also contribute to the expanding pool of macrophages in the liver shortly after birth, when macrophage niches become available during normal organ growth. Thus, like embryonic precursors, monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available to them. Clec4F+ Kupffer cells were isolated and sorted from livers from adult WT mice or KC-DTR or KC-DTR littermate control mice +/- 50ng DT at indicated timepoints. 19 samples (arrays) in total. RNA was isolated, amplified with Nugene pico kit, converted to cDNA and then hybridised on Affymetrix GeneChip Mouse Gene 1.0 ST Arrays.
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Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
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Project description:The TGF-β superfamily member Nodal triggers mesendoderm differentiation in embryonic stem (ES) cells. This transition however requires cooperating Wnt signaling inputs. Here we report that p53, a powerful tumor suppressor in adult tissues, orchestrates this cooperation. We show that p53, which is released from inhibition as mouse ES cells exit from pluripotency, acts as a direct inducer of Wnt3 expression. Wnt-activated Tcf3 then converges with Nodal-activated Smad transcriptional complexes on mesendoderm specification super-enhancers. p53 and its homolog p73 act redundantly in Wnt induction. When p53 and p73 are depleted, the ES cells fail to secrete autocrine Wnt ligands, Tcf and Nodal-activated Smads fail to bind to mesendoderm gene enhancers, and the cells adopt ectoderm rather than mesendoderm identity. Enforced Wnt3 expression or addition of Wnt3a rescues mesendoderm differentiation in p53/p73-depleted ES cells. Thus, independently of their established role as tumor suppressors that guard genome integrity in mature cells, p53 and p73 serve a primordial role in ES cell differentiation by driving a cooperation of Wnt and TGF-β transcriptional inputs on mesendoderm identity gene enhancers.
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Project description:The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during the stressful events surrounding early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
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