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Enteric nervous system neuropathy causes a wide range of severe gut motility disorders. Cell replacement of lost neurons using enteric neural stem cells (ENSC) is a possible therapy for these life-limiting disorders. Here we show rescue of gut motility after ENSC transplantation in a mouse model of human enteric neuropathy, the neuronal nitric oxide synthase ( nNOS −/− ) deficient mouse model, which displays slow transit in the colon. We further show that transplantation of ENSC into the colon rescues impaired colonic motility with formation of extensive networks of transplanted cells, including the development of nNOS + neurons and subsequent restoration of nitrergic responses. Moreover, post-transplantation non-cell-autonomous mechanisms restore the numbers of interstitial cells of Cajal that are reduced in the nNOS −/− colon. These results provide the first direct evidence that ENSC transplantation can modulate the enteric neuromuscular syncytium to restore function, at the organ level, in a dysmotile gastrointestinal disease model. Isolated human and mouse enteric nervous system stem cells (ENSCs) are capable of integrating and promoting innervation of the mouse colon. Here the authors show that transplantation of mouse ENSCs into a mouse model of human enteric neuropathy restores colon motility.

Enteric neuropathies are severe gastrointestinal disorders with unsatisfactory outcomes. We aimed to investigate the potential of enteric neural stem cell therapy approaches for such disorders by transplanting mouse enteric neural crest cells (ENCCs) into ganglionic and aganglionic mouse gut in vivo and analysing functional integration and long-term safety. Neurospheres generated from yellow fluorescent protein (YFP) expressing ENCCs selected from postnatal Wnt1-cre;R26R-YFP/YFP murine gut were transplanted into ganglionic hindgut of wild-type littermates or aganglionic hindgut of Ednrbtm1Ywa mice (lacking functional endothelin receptor type-B). Intestines were then assessed for ENCC integration and differentiation using immunohistochemistry, cell function using calcium imaging, and long-term safety using PCR to detect off-target YFP expression. YFP+ ENCCs engrafted, proliferated and differentiated into enteric neurons and glia within recipient ganglionic gut. Transplanted cells and their projections spread along the endogenous myenteric plexus to form branching networks. Electrical point stimulation of endogenous nerve fibres resulted in calcium transients (F/F0 = 1.16 ± 0.01;43 cells, n = 6) in YFP+ transplanted ENCCs (abolished with TTX). Long-term follow-up (24 months) showed transplanted ENCCs did not give rise to tumours or spread to other organs (PCR negative in extraintestinal sites). In aganglionic gut ENCCs similarly spread and differentiated to form neuronal and glial networks with projections closely associated with endogenous neural networks of the transition zone. Transplanted ENCCs successfully engrafted into recipient ganglionic and aganglionic gut showing appropriate spread, localisation and, importantly, functional integration without any long-term safety issues. This study provides key support for the development and use of enteric neural stem cell therapies.

The 1920s and 30s witnessed an explosion of interest in Spinoza among Zionist intellectuals. The reflexive equation of nation and state has led scholars to conclude that Zionists were drawn to Spinoza because he justified state sovereignty. This assumption is mistaken. Eastern European Zionists rejected Spinoza’s sovereignty-centered political thought—precisely because it denies political standing to non-sovereign bodies such as the kahal. Drawing on diasporic history, Spinoza’s Zionist critics elaborated a distinctive political vision that prized national autonomy but did not equate self-rule with sovereign power. I foreground Zionist repudiation of Spinozist sovereignty to challenge reigning assumptions about the ideological sources of non-sovereign politics. Theorists influenced by German Jewish thought have predicated the cultivation of non-sovereign political imagination on a disavowal of nationalism. This opposition—between diaspora and nation, between nationalism and non-sovereignty—is false. In eastern Europe, nationalist figurations of galut (exile) have long inspired non-sovereign, non-Spinozist political imaginaries.

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning.

[This corrects the article DOI: 10.3389/fnmol.2021.757646.].

Jewish thinkers have long sought to dignify their projects by claiming Spinoza as a progenitor. In recent years, scholars have revived Spinoza’s critique of theocracy as a counter to Judaism’s supposed “antipolitical” tendencies. In this article, I contest lineages that trace admonitions against theocratic “antipolitics” back to Spinoza. When accounting for the resilience of the Hebrew theocracy, Spinoza accords political standing to communities organized on principles other than absolute sovereignty, and he evaluates them in political terms. With this interpretation, I challenge the political conclusions that scholars of Jewish thought have derived from Spinoza. Specifically, I demonstrate that the embrace of sovereignty as a precondition for agency is neither the only political conclusion that one can draw from the critique of theocracy, nor is it the most compelling conclusion for scholars of Jewish politics. I claim an alternative Spinozist legacy to reinvigorate debate about sovereignty’s importance for Jewish political agency.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1 . They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.

In recent years, scholars of Jewish politics have invested political hopes in the revival of “political imagination.” If only we could recapture some of the imaginativeness that early Zionists displayed when wrestling with questions of regime design, it is argued, we might be able to advance more compelling “solutions” to the Israeli-Palestinian conflict. Yet how does one cultivate political imagination? Curiously, scholars who rehearse the catalogue of regimes that Jews have historically entertained seldom pose this question. In this Article, I revisit a historical episode—the appropriation of diasporic historical narratives by Zionists in mandatory Palestine—in an effort to cultivate a richer political imaginary. I analyze the labor Zionist deployment of Simon Dubnow’s influential master narrative, focusing on a 1926 speech in which David Ben Gurion depicts the autonomist regime that he advocates as a variation upon diasporic political practices. On my reading, this episode illustrates the dilemmas that confront thinkers who invest political hopes in regime design. To realize the promise that new political configurations may emerge from reflections upon Jewish history, I argue, we must develop a new account of political agency, once foundational assumptions of the nation-state have been suspended.

As the prospects for a negotiated two-state solution to the Israeli–Palestinian conflict have dwindled, Jewish scholars in the United States have increasingly invoked the concept of diaspora to counter a purported Jewish consensus regarding Zionism. In this essay, I critique prominent exponents of this approach (Judith Butler, Jonathan and Daniel Boyarin) from a diasporic (i.e., non-Zionist) standpoint. My concern is not that Butler and the Boyarins attack Israel publicly, endorse a binational solution to the Israeli–Palestinian conflict, and/or support the movement for Boycott, Divestment, and Sanctions—rather, it is that they lack a compelling vision for diasporic politics. Their visions prove wanting because they contest Zionism on the terrain of Jewish identity. To loosen Zionism's hold, Butler and the Boyarins recover alternative approaches to the attainment or grounding of Jewish identity. Yet when framed as an ethic of particular identity, diasporic thinking can neither rebut Zionism's political arguments, nor can it develop alternative models of Jewish self-rule. Instead of theorizing Jewish identity, I argue, diasporic thinkers should envision Jewish political solidarity beyond the confines of the nation-state.

Histories of political theory have framed the story of the emergence of sovereign states and sovereign selves as a story about secularization—specifically, a story that equates secularization with self-deification. Thomas Hobbes's investment in modesty and humility demonstrates the need for, and the possibility of, an alternative secularization narrative. Scholars have long insisted that “vainglory” is a key term for the interpretation of Leviathan. But Hobbes's task is not complete once he has discredited vainglory. Hobbes must also envision, and cultivate, contrary virtues—and modesty is one virtue that Hobbes would cultivate. An analysis of Hobbes's attempt to redefine and rehabilitate the virtues of modesty shows that Hobbes warns against the temptation to self-deification. In Leviathan, the political task is not to enthrone humans in sovereign invulnerability, but rather to achieve the right balance between bodily security and consciousness of finitude.