The present study used isobaric tags for relative and absolute quantitation (iTRAQ) to identify novel targets in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. The expression of 41 proteins was significantly altered in the inflamed spinal cord. Twenty of these are implicated in EAE for the first time and many have previously been shown to play a role in antigen processing, inflammation, neuroprotection, or neurodegeneration.
In the liver, Wnt/β‐catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl4) toxicity. Following injury, peri‐injury hepatocytes become Wnt‐responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri‐injury Axin2+ hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2+ descendants. Using single‐cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl4 toxicity. Induced loss of β‐catenin in peri‐injury hepatocytes results in delayed repair and ultimately injury‐induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/β‐catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt‐producing regulator of liver tissue repair following localized liver injury.
In the liver, Wnt/β-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl 4 ) toxicity. Following injury, peri-injury hepatocytes become Wntresponsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2 + hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2 + descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl 4 toxicity. Induced loss of β-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/β-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wntproducing regulator of liver tissue repair following localized liver injury. (Hepatology 2019;69:2623-2635).
Multiple sclerosis is an inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Increasing evidence indicates that neuronal pathology and axonal injury are early hallmarks of multiple sclerosis and are major contributors to progressive and permanent disability. Yet, the mechanisms underlying neuronal dysfunction and damage are not well defined. Elucidation of such mechanisms is of critical importance for the development of therapeutic strategies that will prevent neurodegeneration and confer neuroprotection. PMCA2 (plasma-membrane Ca(2+)-ATPase 2) and the NCX (Na(+)/Ca(2+) exchanger) have been implicated in impairment of axonal and neuronal function in multiple sclerosis and its animal models. As PMCA2 and NCX play critical roles in calcium extrusion in cells, alterations in their expression or activity may affect calcium homoeostasis and thereby induce intracellular injury mechanisms. Interventions that restore normal PMCA2 and NCX activity may prevent or slow disease progression by averting neurodegeneration.
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