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Impulses generated by a multicellular, bioelectric signaling center termed the sinoatrial node (SAN) stimulate the rhythmic contraction of the heart. The SAN consists of a network of electrochemically oscillating pacemaker cells encased in a heterogeneous connective tissue microenvironment. Although the cellular composition of the SAN has been a point of interest for more than a century, the biological processes that drive the tissue-level assembly of the cells within the SAN are unknown. Here, we demonstrate that the SAN's structural features result from a developmental process during which mesenchymal cells derived from a multipotent progenitor structure, the proepicardium, integrate with and surround pacemaker myocardium. This process actively remodels the forming SAN and is necessary for sustained electrogenic signal generation and propagation. Collectively, these findings provide experimental evidence for how the microenvironmental architecture of the SAN is patterned and demonstrate that proper cellular arrangement is critical for cardiac pacemaker biorhythmicity.

UnlabelledOBJECT.: Stereotactic radiosurgery (SRS) is an established treatment modality for brain arteriovenous malformations (AVMs) in children, but the optimal treatment parameters and associated treatment-related complications are not fully understood. The authors present their single-institution experience of using SRS, at a relatively low marginal dose, to treat AVMs in children for nearly 20 years; they report angiographic outcomes, posttreatment hemorrhage rates, adverse treatment-related events, and functional outcomes.MethodsThe authors conducted a retrospective review of 2 cohorts of children (18 years of age or younger) with AVMs treated from 1991 to 1998 and from 2000 to 2010.ResultsA total of 80 patients with follow-up data after SRS were identified. Mean age at SRS was 12.7 years, and 56% of patients had hemorrhage at the time of presentation. Median target volume was 3.1 cm(3) (range 0.09-62.3 cm(3)), and median prescription marginal dose used was 17.5 Gy (range 12-20 Gy). Angiograms acquired 3 years after treatment were available for 47% of patients; AVM obliteration was achieved in 52% of patients who received a dose of 18-20 Gy and in 16% who received less than 18 Gy. At 5 years after SRS, the cumulative incidence of hemorrhage was 25% (95% CI 16%-37%). No permanent neurological deficits occurred in patients who did not experience posttreatment hemorrhage. Overall, good functional outcomes (modified Rankin Scale Scores 0-2) were observed for 78% of patients; for 66% of patients, functional status improved or remained the same as before treatment.ConclusionsA low marginal dose minimizes SRS-related neurological deficits but leads to low rates of obliteration and high rates of hemorrhage. To maximize AVM obliteration and minimize posttreatment hemorrhage, the authors recommend a prescription marginal dose of 18 Gy or more. In addition, SRS-related symptoms such as headache and seizures should be considered when discussing risks and benefits of SRS for treating AVMs in children.

Anomalous action potential conduction through the atrial chambers of the heart can lead to severe cardiac arrhythmia. To date, however, little is known regarding the mechanisms that pattern proper atrial conduction during development. Here we demonstrate that atrial muscle functionally diversifies into at least two heterogeneous subtypes, thin-walled myocardium and rapidly conducting muscle bundles, during a developmental window just following cardiac looping. During this process, atrial muscle bundles become enriched for the fast conduction markers Cx40 and Nav1.5, similar to the precursors of the fast conduction Purkinje fiber network located within the trabeculae of the ventricles. In contrast to the ventricular trabeculae, however, atrial muscle bundles display an increased proliferation rate when compared to the surrounding myocardium. Interestingly, mechanical loading of the embryonic atrial muscle resulted in an induction of Cx40, Nav1.5 and the cell cycle marker Cyclin D1, while decreasing atrial pressure via in vivo ligation of the vitelline blood vessels results in decreased atrial conduction velocity. Taken together, these data establish a novel model for atrial conduction patterning, whereby hemodynamic stretch coordinately induces proliferation and fast conduction marker expression, which in turn promotes the formation of large diameter muscle bundles to serve as preferential routes of conduction.

Neurons in the murine olfactory epithelium (OE) differ by the olfactory receptor they express as well as other molecular phenotypes that are regionally restricted. These patterns can be precisely regenerated following epithelial injury, suggesting that spatial cues within the tissue can direct neuronal diversification. Nonetheless, the permanency and mechanism of this spatial patterning remain subject to debate. Via transplantation of stem and progenitor cells from dorsal OE into ventral OE, we demonstrate that, in mice of both sexes, nonautonomous spatial cues can direct the spatially circumscribed differentiation of olfactory sensory neurons. The vast majority of dorsal transplant-derived neurons express the ventral marker OCAM (NCAM2) and lose expression of NQO1 to match their new location. Single-cell analysis also demonstrates that OSNs adopt a fate defined by their new position following progenitor cell transplant, such that a ventral olfactory receptor is expressed after stem and progenitor cell engraftment. Thus, spatially constrained differentiation of olfactory sensory neurons is plastic, and any bias toward an epigenetic memory of place can be overcome. [ABSTRACT FROM AUTHOR]

Neurons in the murine olfactory epithelium (OE) differ by the olfactory receptor they express as well as other molecular phenotypes that are regionally restricted. These patterns can be precisely regenerated following epithelial injury, suggesting that spatial cues within the tissue can direct neuronal diversification. Nonetheless, the permanency and mechanism of this spatial patterning remain subject to debate. Via transplantation of stem and progenitor cells from dorsal OE into ventral OE, we demonstrate that, in mice of both sexes, nonautonomous spatial cues can direct the spatially circumscribed differentiation of olfactory sensory neurons. The vast majority of dorsal transplant-derived neurons express the ventral marker OCAM (NCAM2) and lose expression of NQO1 to match their new location. Single-cell analysis also demonstrates that OSNs adopt a fate defined by their new position following progenitor cell transplant, such that a ventral olfactory receptor is expressed after stem and progenitor cell engraftment. Thus, spatially constrained differentiation of olfactory sensory neurons is plastic, and any bias toward an epigenetic memory of place can be overcome. SIGNIFICANCE STATEMENT Spatially restricted differentiation of olfactory sensory neurons is both key to normal olfactory function and a challenging example of biological specificity. That the stem cells of the olfactory epithelium reproduce the organization of the olfactory periphery to a very close approximation during lesion-induced regeneration begs the question of whether stem cell-autonomous genomic architecture or environmental cues are responsible. The plasticity demonstrated after transfer to a novel location suggests that cues external to the transplanted stem and progenitor cells confer neuronal identity. Thus, a necessary prerequisite is satisfied for using engraftment of olfactory stem and progenitor cells as a cellular therapeutic intervention to reinvigorate neurogenesis whose exhaustion contributes to the waning of olfaction with age., (Copyright © 2019 the authors 0270-6474/19/390814-19$15.00/0.)