RESUMO
The heart develops in a synchronized sequence of proliferation and differentiation of cardiac progenitor cells (CPCs) from two anatomically distinct pools of cells, the first heart field (FHF) and second heart field (SHF). Congenital heart defects arise upon dysregulation of these processes, many of which are restricted to derivatives of the FHF or SHF. Of the conserved set of signaling pathways that regulate development, the Wnt signaling pathway has long been known for its importance in SHF development. The source of such Wnts has remained elusive, though it has been postulated that these Wnts are secreted from ectodermal or endodermal sources. The central question remains unanswered: Where do these Wnts come from? Here, we show that CPCs autoregulate SHF development via Wnt through genetic manipulation of a key Wnt export protein (Wls), scRNA-seq analysis of CPCs, and use of our precardiac organoid system. Through this, we identify dysregulated developmental trajectories of anterior SHF cell fate, leading to a striking single ventricle phenotype in knockout embryos. We then applied our findings to our precardiac organoid model and found that Wnt2 is sufficient to restore SHF cell fate in our model of disrupted endogenous Wnt signaling. In this study, we provide a basis for SHF cell fate decision-proliferation vs. differentiation-autoregulated by CPCs through Wnt.
Assuntos
Cardiopatias Congênitas , Coração , Humanos , Coração/fisiologia , Diferenciação Celular , Via de Sinalização Wnt , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Regulação da Expressão Gênica no DesenvolvimentoRESUMO
The Notch pathway is an ancient intercellular signaling system with crucial roles in numerous cell-fate decision processes across species. While the canonical pathway is activated by ligand-induced cleavage and nuclear localization of membrane-bound Notch, Notch can also exert its activity in a ligand/transcription-independent fashion, which is conserved in Drosophila, Xenopus, and mammals. However, the noncanonical role remains poorly understood in in vivo processes. Here we show that increased levels of the Notch intracellular domain (NICD) in the early mesoderm inhibit heart development, potentially through impaired induction of the second heart field (SHF), independently of the transcriptional effector RBP-J. Similarly, inhibiting Notch cleavage, shown to increase noncanonical Notch activity, suppressed SHF induction in embryonic stem cell (ESC)-derived mesodermal cells. In contrast, NICD overexpression in late cardiac progenitor cells lacking RBP-J resulted in an increase in heart size. Our study suggests that noncanonical Notch signaling has stage-specific roles during cardiac development.
Assuntos
Coração/embriologia , Miocárdio/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Diferenciação Celular , Células Cultivadas , Fator de Transcrição GATA4/genética , Fator de Transcrição GATA4/metabolismo , Proteína Homeobox Nkx-2.5/genética , Proteína Homeobox Nkx-2.5/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Mesoderma/citologia , Mesoderma/embriologia , Mesoderma/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Miocárdio/citologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Carbon Capture, Utilization, and Storage (CCUS) is an important potential technical way for coal power plants to achieve near-zero carbon emissions with the current energy structure in China being dominated by coal. However, CCUS is still at the early demonstration stage, and there are many uncertainties in the business model and policy incentives that the traditional method can no longer handle. At the same time, few studies have analyzed these issues. Taking coal-fired power plants as the research object, we adopt the system dynamics method (SD) to compare the economic feasibility, stability, and CO2 emission reduction effect of the CCUS in the vertical integration model and the CCUS operator model. Furthermore, this paper also studies the effect of different incentive policies on CCUS. Results show the following: (1) Both models are economically viable. From the stability perspective, the CCUS operator model is superior to the vertical integration model. (2) In terms of the effect of individual policies, the government's preference for subsidies to the coal-fired power plant can significantly reduce CO2 emissions. Increasing the additional government subsidy and carbon tax can accelerate the CCUS system into a relatively stable state, but beyond a certain range, the marginal CO2 capture rate, marginal CO2 emission reduction rate, and marginal profit rate of each department will be significantly reduced. The storage enterprise highly depends on the government subsidy. Low government subsidy allocation, low additional government subsidy, and a low carbon tax will lead to continuous negative profits for the storage enterprise, making the CCUS system unsustainable. (3) The impact of combination policies on CCUS is not simply the sum of the effects of individual policies. Each policy has a counteracting or reinforcing effect on the other.
Assuntos
Carbono , Motivação , Dióxido de Carbono/análise , Estudos de Viabilidade , Carvão Mineral , Centrais ElétricasRESUMO
In this paper, single-layer and bulk 316 L selective laser melting (SLM) experiments were conducted, fine submicron-scale geometric symmetrical cellular (hexagonal, pentagonal and square), elongated cellular and bands solidification morphologies were found in the laser-melt top surface. Meanwhile, morphological developed sub-grain patterns with quasi-hexagonal cellular, elongated cellular and bands structures (size ~1 µm) coexisting inside one single macro-solidified grain were also identified. This demonstrated the transitions from quasi-hexagonal-cells to elongated cells/bands, and transitions reverse, occurred in the whole bulk under some circumstances during SLM. Based on the experimental realities, these morphologies are formed by the local convection and Bénard instabilities in front of the solid/liquid interface (so-called mushy zones) affected by intricate temperature and surface tension gradients. Quasi-hexagonal cellular convective fields are then superimposed on macro-grain solidification to form the sub-grain patterns and micro-segregations. This explanation seems reasonable and is unifying as it can be expanded to other eutectic alloys with face center cubic (FCC) prevenient phase prepared by SLM, e.g., the Al-Si and Co-Cr-Mo systems.