Fig 1: Working model of the action of PEDF + DHA in enhancing corneal nerve regeneration. PEDF via its 44-mer neuroprotective domain (in red) activates PEDF-R in the cornea (amplify for clarification). This transmembrane receptor with iPLA2 activity released DHA, enriched in the sn-2 position of membrane phospholipids, by DHA supplementation. Mouse corneas express a 12- and 15-lipoxygenase (LOX) (55); DHA is converted to 17-HpDHA on the pathway to NPD1 by 15-LOX-1, and DHA is also converted to 14-HpDHA on the pathway to maresin-1 by 12-LOX-1. Docosanoids such as NPD1 (and possibly others not yet identified) induce the gene expression and protein levels of the neurotrophins NGF, BDNF, and Sema7A (all of which are secreted to tears), and of RAGs vip, npy, and sprr1a in the TG. Phosphorylation of TrkB and ERK 1/2 occurs in the TG as a result of BDNF and Sema7A secretion in the tear film. Inhibition of the phospholipase activity of the PEDF-R abolishes this signaling mechanism and corneal nerve regeneration.
Fig 2: Spatial transcriptomics reveals the phenotypic trajectory of the intracardiac resolving intracardiac scar and border zone. (A) Pseudotime developmental trajectory was integrated with biological process enrichment to identify the regional identity of the 5 intracardiac scar states. (B) Uniform manifold approximation and projection reveals 5 distinct transcriptional clusters that define the temporal progression of the intracardiac scar, the border zone, and the epicardium. (C) Barcoded spots were mapped back to an anatomical origin to spatially and temporally resolve the intracardiac scar identity, and location of the border zone as a narrow band of tissue between the injury and healthy myocardium. (D) Spatially resolved Sprr1a expression reveals an enrichment within the border zone specifically at 3 and 7 dpi. (E) Representative heart sections obtained at indicated post-injury timepoints were stained with antibodies directed against Troponin I (cardiomyocytes, red) and Sprr1a (green). DAPI labels nuclei, and the dashed line indicates transition from injury to healthy myocardium, defined as the border zone. Note the enrichment of Sprr1a in border zone cardiomyocytes at 3 dpi and 7 dpi, which is absent in remote myocardium. (F) Schematic of the proposed stages of neonatal mouse heart regeneration, based on bulk RNA-sequencing of isolated fibroblasts and spatial transcriptomics at key regenerative timepoints. Scale bar = 1 mm (C,D) and 100 mm (E).
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