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In this issue we offer brief synopses of four papers: a Review highlighting new in situ metabolomics-related tools for adrenal research, and Original Articles reporting a novel animal model for studying wound repair, a comprehensive stereologic assessment of systemic iron overload on pulmonary ultrastructure, and the use of bone marrow-derived mesenchymal cells as potential therapy for sepsis-induced liver injury.
Adrenal research goes in situ metabolomics
An international team of authors (Papathomas et al. 2019) provides a most up-to-date review on novel metabolomics-related methodologies in adrenal research (see cover image). Since the adrenal glands are key regulators for mineral balance, glucose metabolism and early sexual differentiation, as well as rapid response to stress, evaluation of metabolic processes is critical in adrenal physiology and disease. The authors focus on (1) in situ metabolomics by mass spectrometry imaging (MALDI-MSI); (2) steroid metabolomics by gas and liquid chromatography–mass spectrometry of adrenocortical neoplastic and non-neoplastic disease; (3) energy pathway metabologenomics by liquid chromatography–mass spectrometry-based metabolomics of Krebs cycle intermediates in phaeochromocytoma and paraganglioma; and (4) cellular reprogramming to generate functional steroidogenic cells and hence to modulate the steroid metabolome. Moreover, emerging clinical applications towards diagnostic, prognostic, predictive and therapeutic biomarkers in tumors arising from the adrenal gland and extra-adrenal paraganglia are highlighted. It is concluded that these techniques are of tremendous value in the era of metabolomics-driven precision medicine by providing cell-specific molecular signatures that complement histopathological, immunohistochemical and a variety of other molecular data.
Time heals all wounds…
The healing of a skin wound is a complex process involving initial inflammation, followed by formation and remodeling of new tissue (Gurtner et al. 2008). Rodent models, such as mouse and rat have been used in the past to study wound healing mechanisms, and now Lee and colleagues (2019) have investigated using the Mongolian gerbil as a model for this healing process as well. For these studies, the authors compared the wound healing process occurring in gerbil skin with that of the mouse occurring over a period of up to 14 days. They used multiple analysis techniques including histology, immunohistochemistry, and RNA sequencing and RT-PCR. They found that skin wound healing, induced by excision wounds on the backs of the animals, displayed some differences between the two animal models. Although early wound closure was observed to be similar between the two species, the expression of key molecules involved in the wound repair process was found to differ. Specifically, the expression of TGF-β1 was downregulated in the gerbil during the early phases of wound healing compared to the mouse. Interestingly, during the same time period, the expressions of both TGF-β2 and TGF-β3 were upregulated in the gerbil, likely as a compensatory response for the decreased levels of TGF-β1. Similarly, various integrins involved in re-epithelialization and myofibroblast differentiation in the gerbil were either upregulated or downregulated compared to the mouse during the early wound healing process. The gerbil model also displayed a large number of newly produced hair follicles in the wounded dermis, greater expression of α-smooth muscle actin-positive cells in the wound, and diminished collagen deposition all compared to the mouse model. To summarize, the authors have defined the Mongolian gerbil as a novel skin wound healing model, displaying unique aspects of the healing process compared to the common mouse model.
(Iron)ing out the details of pulmonary effects from systemic iron overload
The effects of iron accumulation in the lungs is an area of great interest due to its potential pathological consequences (Ganz 2017). Iron homeostasis is dependent upon the hepcidin/ferroportin regulatory system, whereby an increased expression of hepatic hepcidin triggered by elevated levels of systemic iron is bound by the transmembrane ferroportin, resulting in internalization and removal of iron from the systemic circulation. Since disruption in the hepcidin/ferroportin regulatory system can result in human disease, such as human hereditary hemochromatosis type 4, a genetic mouse model of this disease was recently utilized to analyze its effect on pulmonary function and accumulation of excess iron in the lung (Neves et al. 2017). This same group has now expanded upon this earlier investigation by focusing specifically on the effect of systemic iron overload on the alveolar region of the lung (Muhlfeld et al. 2019). They performed a sophisticated stereologic investigation to assess the subcellular localization of iron accumulation in the lung alveolus, as well as determining multiple morphologic parameters in wildtype and the knockout mouse model of hereditary hemochromatosis type 4 (Slc-40a1C326S/C326S). To summarize a large amount of ultrastructural and stereologic data, the authors found: (1) iron accumulated in alveolar epithelial type I cells (AE1) and not in alveolar epithelial type II cells (AE2) as previously believed; and (2) the knockout animals possessed a thicker air–blood barrier, a lower alveolar volume, a greater number of AE2 cells, and finally a lower lamellar body volume in AE2 cells compared to the wildtype animals. Interestingly, the increased blood-air barrier displayed by the knockout animals may explain the oxygen deficit measured for these animals in a previous study (Neves et al. 2017). This study once again illustrates the strength and necessity of carefully planned design-based stereologic approaches to accurately assess morphological alterations manifested by experimental treatments.
Stem cells for the improvement of sepsis-induced liver injury
Sepsis is a condition characterized by serious systemic inflammation and multiple organ dysfunction/failure syndromes with the liver being prominently affected (Cohen 2002). A main response to sepsis is the enhanced production of inflammatory cytokines and reactive oxygen species as well as the activation of coagulation pathways (Lolis and Bucala 2003). Mesenchymal stem cells have been shown to modulate the innate and adaptive immune system (Zhang et al. 2014). Therefore, Selim et al. (2019) have conducted a study to clarify the possible effect of bone marrow-derived mesenchymal stem cells on liver injury in a rat model of lipopolysaccharide-induced sepsis. They performed a light and electron microscopic as well as immunohistochemical investigation combined with biochemical and molecular analyses. The intraperitoneal injection of mesenchymal stem cells and their homing to the liver resulted in a reduced degree of sepsis-induced liver damage, in enhanced regeneration and reduced apoptosis. Furthermore, the nuclear factor-erythroid 2-related factor 2 was significantly increased and this was associated with a decreased level of inflammatory cytokines and the normalization of the level of the anti-oxidants glutathione peroxidase and reduced glutathione. Together, these results demonstrate that the beneficial effect of mesenchymal stem cell treatment on sepsis-induced liver damage is mediated by increased nuclear factor-erythroid 2-related factor 2 signaling and indicate the potential of this treatment for therapy.
- Muhlfeld C, Neves J, Brandenberger C, Hegermann J, Wrede C, Altamura S, Muckenthaler MU (2019) Air-blood barrier thickening and alterations of alveolar epithelial type 2 cells in mouse lungs with disrupted hepcidin/ferroportin regulatory system. Histochem Cell Biol. https://doi.org/10.1007/s00418-018-1737-y Google Scholar