Drosophila heart cell movement to the midline occurs through both cell autonomous migration and dorsal closure.

The Drosophila heart is a linear organ formed by the movement of bilaterally specified progenitor cells to the midline and adherence of contralateral heart cells. This movement occurs through the attachment of heart cells to the overlying ectoderm which is undergoing dorsal closure. Therefore heart cells are thought to move to the midline passively. Through live imaging experiments and analysis of mutants that affect the speed of dorsal closure we show that heart cells in Drosophila are autonomously migratory and part of their movement to the midline is independent of the ectoderm. This means that heart formation in flies is more similar to that in vertebrates than previously thought. We also show that defects in dorsal closure can result in failure of the amnioserosa to properly degenerate, which can physically hinder joining of contralateral heart cells leading to a broken heart phenotype.

Impairment of in vivo calcium signaling in amyloid plaque-associated microglia.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) both in man and in multiple mouse models, and epidemiological studies link the use of anti-inflammatory drugs with a reduced risk of developing the disease. AD-related neuroinflammation is largely mediated by microglia, the main immune cells of the central nervous system. In vitro, executive functions of microglia are regulated by intracellular Ca(2+) signals, but little is known about microglial Ca(2+) signaling in vivo. Here we analyze in vivo properties of these cells in two mouse models of AD. In both strains plaque-associated microglia had hypertrophic/amoeboid morphology and were strongly positive for markers of activation such as CD11b and CD68. Activated microglia failed to respond reliably to extracellular release of adenosine triphosphate (ATP, mimicking tissue damage) and showed an increased incidence of spontaneous intracellular Ca(2+) transients. These Ca(2+) transients required activation of ATP receptors and Ca(2+) release from the intracellular Ca(2+) stores, and were not induced by neuronal or astrocytic hyperactivity. Neuronal silencing, however, selectively increased the frequency of Ca(2+) transients in plaque-associated microglia. Thus, our in vivo data reveal substantial dysfunction of plaque-associated microglia and identify a novel Ca(2+) signal possibly triggering a Ca(2+)-dependent release of toxic species in the plaque vicinity.

Microglia and Stem-Cell Mediated Neuroprotection after Neonatal Hypoxia-Ischemia.

Neonatal hypoxia-ischemia encephalopathy (HIE) refers to a brain injury in term infants that can lead to death or lifelong neurological deficits such as cerebral palsy (CP). The pathogenesis of this disease involves multiple cellular and molecular events, notably a neuroinflammatory response driven partly by microglia, the brain resident macrophages. Treatment options are currently very limited, but stem cell (SC) therapy holds promise, as beneficial outcomes are reported in animal studies and to a lesser degree in human trials. Among putative mechanisms of action, immunomodulation is considered a major contributor to SC associated benefits. The goal of this review is to examine whether microglia is a cellular target of SC-mediated immunomodulation and whether the recruitment of microglia is linked to brain repair. We will first provide an overview on microglial activation in the rodent model of neonatal HI, and highlight its sensitivity to developmental age. Two complementary questions are then addressed: (i) do immune-related treatments impact microglia and provide neuroprotection, (ii) does stem cell treatment modulates microglia? Finally, the immune-related findings in patients enrolled in SC based clinical trials are discussed. Our review points to an impact of SCs on the microglial phenotype, but heterogeneity in experimental designs and methodological limitations hamper our understanding of a potential contribution of microglia to SC associated benefits. Thorough analyses of the microglial phenotype are warranted to better address the relevance of the neuroimmune crosstalk in brain repair and improve or advance the development of SC protocols in humans.