Biology subjects

Bachar-Wikstrom, E.

Publications and source records attributed to Bachar-Wikstrom, E..

3 recordsLinked to original sources

bioRxiv2025

Mitophagy upregulates WNT5A/Ca2+ signalling to accelerate fibroblast migration and wound healing

In the event of dysregulated wound healing, hard-to-heal chronic wounds form and can place a significant burden on healthcare systems, yet gaps in knowledge surrounding the cellular and molecular processes involved have resulted in a lack of effective treatments. Here, we show that ubiquitin-independent mitophagy is upregulated in the early- and mid-wound healing stages. Additionally, enhancing mitophagy through Urolithin A treatment improved wound healing, in particular by accelerating fibroblast migration. RNAseq analysis demonstrated an upregulation of non-canonical WNT5A signalling in Urolithin A-treated fibroblasts, which was underpinned by elevated cytosolic Ca2+ buffering and CREB phosphorylation, ultimately leading to enhanced actin polymerisation and fibroblast migration. This study is thus the first to elucidate a role for mitophagy specifically in fibroblasts during wound healing; to demonstrate an important role for mitophagy in Ca2+-mediated WNT5A signalling cascades; and indicate the potential therapeutic benefits of treating non-healing wounds with mitophagy inducers such as Urolithin A.

developmental biology↗

bioRxiv2025

Mitophagy promotes metabolic reprogramming to enhance keratinocyte migration via ANGPTL4 during wound healing

Mitochondrial function and quality control is emerging as a key regulator of keratinocyte migration in both wounding and non-wound healing contexts, yet the cellular mechanisms that support this process are incompletely understood. In this study, using single-cell RNA sequencing data of human wounded tissue we identified a distinct population of migrating keratinocytes marked by the high expression of the mitophagy regulator BNIP3 during the proliferative stage of wound healing. Pharmacological induction of mitophagy with Urolithin A accelerated keratinocyte migration in vitro as well as keratinocyte function and regeneration in aged zebrafish, whilst RNA sequencing of primary human keratinocytes revealed the transcriptional upregulation of ANGPTL4 in Urolithin-A treated cells. Mechanistically, Urolithin A increased metabolic switching to a more glycolytic phenotype, leading to AKTGSK3 pathway activity and FOSL1-mediated ANGPTL4 transcription, ultimately promoting keratinocyte migration through enhanced laminin-332 production. Overall, our findings uncover a novel role for mitophagy in promoting keratinocyte migration during wound repair, and demonstrate that pharmacologically enhancing mitophagy promotes regenerative epithelial responses by enhancing FOSL1-mediated ANGPTL4 signalling through the modulation of metabolic switching. These insights significantly expand the understanding of the role of mitophagy on keratinocyte function during wound healing, linking mitophagy to metabolic adaption in keratinocytes, and provide a mechanistic basis for targeting mitophagy or downstream genes in wound healing therapies.

developmental biology↗

bioRxiv2024

Characterization of liver-pancreas crosstalk following beta-cell loss reveals a role for the molybdenum cofactor in beta-cell regeneration

Regeneration of insulin-producing {beta}-cells is an alternative avenue to manage diabetes, and it is crucial to unravel this process in vivo during physiological responses to the lack of {beta}-cells. Here, we aimed to characterize how hepatocytes can contribute to {beta}-cell regeneration in a zebrafish model of {beta}-cell ablation. Using lineage-tracing, we show that hepatocytes do not directly convert into {beta}-cells even under extreme {beta}-cell ablation conditions. A transcriptomics analysis of isolated hepatocytes following {beta}-cell ablation displayed altered lipid- and glucose-related processes. Based on the transcriptomics, we performed a genetic screen that uncovers a potential role for the molybdenum cofactor (Moco) biosynthetic pathway in {beta}-cell regeneration and glucose metabolism in zebrafish. Consistently, Mocs2 haploinsufficiency in mice indicated dysregulated glucose metabolism and liver function. Together, our study sheds light on the liver-pancreas crosstalk and suggests that the molybdenum cofactor biosynthesis pathway should be further studied in relation to glucose metabolism and diabetes.

developmental biology↗