TAM Receptors in the Pathophysiology of Liver Disease

TAM receptors (Tyro3, Axl and MerTK) are a family of tyrosine kinase receptors that are expressed in a variety of cell populations, including liver parenchymal and non-parenchymal cells. These receptors are vital for immune homeostasis, as they regulate the innate immune response by suppressing inflammation via toll-like receptor inhibition and by promoting tissue resolution through efferocytosis. However, there is increasing evidence indicating that aberrant TAM receptor signaling may play a role in pathophysiological processes in the context of liver disease. This review will explore the roles of TAM receptors and their ligands in liver homeostasis as well as a variety of disease settings, including acute liver injury, steatosis, fibrosis, cirrhosis-associated immune dysfunction and hepatocellular carcinoma. A better understanding of our current knowledge of TAM receptors in liver disease may identify new opportunities for disease monitoring as well as novel therapeutic targets. Nonetheless, this review also aims to highlight areas where further research on TAM receptor biology in liver disease is required.

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni’s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.

Maternal high-fat diet in mice induces cerebrovascular, microglial and long-term behavioural alterations in offspring

Various environmental exposures during pregnancy, like maternal diet, can compromise, at critical periods of development, the neurovascular maturation of the offspring. Foetal exposure to maternal high-fat diet (mHFD), common to Western societies, has been shown to disturb neurovascular development in neonates and long-term permeability of the neurovasculature. Nevertheless, the effects of mHFD on the offspring’s cerebrovascular health remains largely elusive. Here, we sought to address this knowledge gap by using a translational mouse model of mHFD exposure. Three-dimensional and ultrastructure analysis of the neurovascular unit (vasculature and parenchymal cells) in mHFD-exposed offspring revealed major alterations of the neurovascular organization and metabolism. These alterations were accompanied by changes in the expression of genes involved in metabolism and immunity, indicating that neurovascular changes may result from abnormal brain metabolism and immune regulation. In addition, mHFD-exposed offspring showed persisting behavioural alterations reminiscent of neurodevelopmental disorders, specifically an increase in stereotyped and repetitive behaviours into adulthood.

Osthole Blocks HMGB1 Release From the Nucleus and Confers Protective Effects Against Renal Ischemia-Reperfusion Injury

Renal ischemia-reperfusion (IR) is one of the main causes of renal injury. In severe cases with serious consequences, IR-related renal damage progresses rapidly and can even lead to acute renal failure. Its clinical treatment is currently difficult. According to various studies at home and abroad, HMGB1 is released from the nucleus into the cytoplasm or extracellular space by damaged parenchymal cells during ischemia and hypoxia, and this plays an important role in the initiation of reperfusion injury as an early inflammatory factor and is closely related to the occurrence and development of renal diseases. In recent years, the protective effect of osthole on IR of tissues and organs has been a key topic among clinical researchers. Osthole can inhibit the inflammatory response, reduce cell apoptosis the progression, and improve the prognosis of IR, thus protecting the kidney. During the development of renal IR, finding a mechanism through which the osthole blocks the release of HMGB1 from the nucleus would be helpful in detecting targets for clinical treatment.

SOME TOPOGRAPHICAL AND HISTOLOGICAL STUDIES OF THYROID AND PARATHYROD GLANDS OF MOORHEN (Gallinula c. chloropus)

The thyroid gland of Moorhen has two separated lobes. These lobes were located in the throracic inlet and receive blood supply from the cranial, middle and caudal thyroid arteries. The histological organization of the thyroid gland in Moorhen is surrounded by a distinct connective tissue capsule and the parenchymal cells were arranged into colloid filled follicles enmeshed in the highly vascular interstitial connective tissue. The bilaterally paired, round to oval, parathyroid glands in Moorhen were located intrathoracically near or close to the caudal pole of the thyroid glands. They receive blood by short branches from caudal thyroid artery and small branch from the common carotid artery. The parathyroid glands in Moorhen have a thin connective tissue capsule. Its parenchymal cells were arranged into an irregular, anastomosing cords of chief cells. No oxyphil cells were found in the parathyroid glands of Moorhen.

A single-cell atlas of mouse lung development

ABSTRACT Lung organogenesis requires precise timing and coordination to effect spatial organization and function of the parenchymal cells. To provide a systematic broad-based view of the mechanisms governing the dynamic alterations in parenchymal cells over crucial periods of development, we performed a single-cell RNA-sequencing time-series yielding 102,571 epithelial, endothelial and mesenchymal cells across nine time points from embryonic day 12 to postnatal day 14 in mice. Combining computational fate-likelihood prediction with RNA in situ hybridization and immunofluorescence, we explore lineage relationships during the saccular to alveolar stage transition. The utility of this publicly searchable atlas resource (www.sucrelab.org/lungcells) is exemplified by discoveries of the complexity of type 1 pneumocyte function and characterization of mesenchymal Wnt expression patterns during the saccular and alveolar stages – wherein major expansion of the gas-exchange surface occurs. We provide an integrated view of cellular dynamics in epithelial, endothelial and mesenchymal cell populations during lung organogenesis.

The Endothelial Barrier Restricts Endocrine Actions to the Luminal Vascular Receptors: Changing the Paradigm: A Didactic Approach

In 1849, the first list of endocrine hormones was discovered and proposed that the synthesizing gland delivers it to the circulation. The circulatory hormone reaches the target organ, physically unimpeded acts directly on the parenchymal cells. Such a simplistic view persists despite new knowledge of an endothelial wall barrier and implications for every parenchymal cell in the body. This misconception leads to inadequate interpretations of data, wrong diagnosis and therapeutic expectations, erroneous hypotheses, and misleads further research work. The quest of this review is to play down this misconception by pointing out key overlooked findings of the vascular endothelial wall: 1) The selective endothelial barrier physically separates two same-hormone-containing compartments; the endocrine and the interstitial autocrine hormone compartments, 2) the hormone concentrations values in these compartments are independent of each other, 3) in each compartment the hormone acts solely on the receptors of that particular compartment, 4) multiple intravascular endocrine hormones act solely on their corresponding luminal endothelial membrane receptor (LEMR), without directly acting on the parenchymal cells, 5) Agonist-activation of LEMR triggers the release of specific paracrine endothelial agents that in conjunction with autocrine interstitial hormone modulate parenchymal function(s) and perhaps the turnover of the interstitial autocrine hormone, 6) these hormone compartments, functionally interact via paracrine exchange signaling, and the integrated intercourse of all these events result in the final hormonal organ effect. The present challenges to achieving more rationale therapeutic effects are to design agonists or antagonists that exclusively gain access to a target compartment and have high specificity for the receptor of the cells in that compartment.

TAMI-36. TAMEP ARE BRAIN TUMOR PARENCHYMAL CELLS CONTROLLING NEOPLASTIC ANGIOGENESIS AND PROGRESSION

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor-parenchymal cells may promote specific phases of disease-progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Strikingly, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell-population, by conditional Sox2-knockout, drastically reduced glioblastoma-vascularization and -size. TAMEP manipulation profoundly altered vessel function and strongly attenuated the blood-tumor barrier. Hence, our data indicate TAMEP and their progenitors as new targets for glioblastoma therapy.

IS THE FLOWER OF PULASAN (NEPHELIUM RAMBOUTAN-AKE) A PROTOGYNY OR PROTANDRY?

Pulasan is an androdioecious plant that has both male and hermaphrodite flowers on separate plants. The objectives of this study were to obtain data about the anatomical structure of pulasan flower and to investigate whether the pistil and the stamens of pulasan flower reach maturity at different times. The anatomical observation was done on compound flowers taken from three male trees and three hermaphrodite trees. Two compound flowers that still in buds, about to bloom and fully bloom were picked from each tree. Flowers were observed in a cross and longitudinal section. The results showed that the sepals of pulasan flower comprised of the uniseriate epidermis and multilayered polyhedral parenchymal cells. Stamen development started from the anther followed by the formation of the filament. The pollen of hermaphrodite pulasan flowers reached maturation earlier than the pistil. The pistil development started from the expansion of meristem cells in the center of the flower and ends with the warp of the stigma.