No abstract

The attachment of Schistosoma mansoni cercariae to mammalian skin is specifically stimulated by L-arginine. As L-arginine is an unsuitable signal for a specific identification of mammalian skin we examined the following 5 hypotheses to explain the advantage of the cercarial sensitivity to L-arginine. (1) A Schistosoma infection lowered the arginine concentration in the serum of mice, and this could enable the cercariae to avoid attachments to already infected mice. However, the infection did not reduce the arginine concentration in the skin and the cercarial attachment responses to it. (2) Creeping cercariae showed chemotactic orientation specifically along increasing L-arginine gradients. L-arginine could act as a pheromone which could guide cercariae towards common penetration sites. However, the cercarial acetabular gland contents were not attractive and they did not (in contrast to previous reports) contain much arginine. (3) Schistosomula (transformed cercariae) could use L-arginine to produce nitric oxide (NO) for blood vessel dilation during their migration in the host. However, in vitro the transformed cercariae did not convert L-arginine into citrulline and NO. (4) Schistosomula could bind L-arginine from the surrounding tissues and so escape the cellular immune attack (which needs L-arginine as the precursor of NO). However, transformed cercariae bound no more L-arginine than L-serine and L-lysine. (5) Schistosomula, migrating parallel to the surface in the mammalian epidermis, are dependent on information on their position between the inner and the surface layers of the skin. In the mouse skin, they adjusted their body axis with the ventral side toward the deeper (arginine-residue rich) epidermis layers. When migrating in agar, they showed chemo-orientation toward serum, and D-glucose and L-arginine were the stimulating compounds therein. The burrowing schistosomula adjusted their body axis (as in the epidermis) with the ventral side toward the higher concentration of L-arginine and not of glucose. We argue that the sensitivity for L-arginine has its primary function in orientation within mammalian skin and in location of blood vessels.

Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.

Stojanović et al. Vascular Smooth Muscle Cell Senescence deregulation to warrant senescent VSMC detection, we have conducted a non-biased proteomics and in silico analysis of RS VSMC demonstrating altered RNA biology as the central molecular feature of senescence in this cell type. Therefore, key proteins involved with RNA functionality, HMGB-1 release, LMNB-1 downregulation, in junction with nuclear enlargement, can be used as markers of VSMC senescence, enabling the detection of these pathogenic pro-inflammatory cells in future therapeutic studies in ischemic heart disease and atherosclerosis.