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WNT signaling memory is required for ACTIVIN to function as a morphogen

ABSTRACT: It has now become clear that the process of fate specification during early embryogenesis is mediated by a handful of key signaling pathways. However, how the temporal and spatial integration of these signals plays out to give rise to self-organization of tissues remains obscure. Here we use artificial human gastruloids and quantitative single-cell analysis to dissect the temporal integration of two key pathways WNT and ACTIVIN that along with BMP control gastrulation and primitive streak patterning in model systems. We showed that ACTIVIN elicits a transient signaling response, as well as a transient induction of differentiation. However, unlike BMP and WNT, ACTIVIN cannot induce stable primitive streak formation and mesodermal patterning. Pre-exposure to WNT switches the response of cells to ACTIVIN whereby it becomes a concentration dependent morphogen. This provides evidence for WNT signaling memory that occurs at the transcriptional level and not as a modifier of ACTIVIN signaling dynamics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111717 | GEO | 2018/10/22

REPOSITORIES: GEO

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Project description:Cardiovascular diseases are a major cause of life-threatening burden around the world. The heart has a very low regeneration capacity and donor organs for transplantation are scarce. Therefore regeneration of lost myocardium with stem cell-derived cardiomyocytes (CMs) provides an attractive strategy for heart repair. Human pluripotent stem cells (hPSCs) can be efficiently differentiated in vitro into CMs but the molecular mechanisms behind this process are still not fully understood. In particular identification of secreted autocrine and/or paracrine factors that function as important extrinsic signals remained elusive because the mass spectrometry (MS)-based identification of secreted proteins from cell culture supernatants is impeded by high levels of albumin present in common differentiation media. Thus we established an albumin-free cardiomyogenic differentiation medium and performed secretomics at seven different time points during in vitro differentiation. This analysis led to the identification of 4832 proteins with 1802 being significantly altered during differentiation and 431 of these were annotated as secreted according to gene ontology. Bioinformatics revealed enrichment of extrinsic Wnt pathway-related proteins 3 days upon induction of differentiation and of extracellular matrix proteins in the resulting CMs. Numerous extrinsic components of Wnt, Activin A, Nodal, TGFβ, BMP or FGF signaling pathways were quantitatively assessed during differentiation. Notably, the abundance of pathway agonists was generally lower compared to the respective antagonists but their curves of progression over timer were rather similar. We hypothesize that Activin A, Nodal and TGFβ signaling are turned down shortly upon initiation of cardiac differentiation whereas BMP signaling is switched on. Wnt and FGF signaling peaks between d0 and d3 of differentiation and interestingly, Activin A and TGFβ signaling seem to be reactivated at the cardiac progenitor stages and/or in early CMs.

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WNT signaling memory is required for ACTIVIN to function as a morphogen

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