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Ryou, H.

Publications and source records attributed to Ryou, H..

2 recordsLinked to original sources

Germline status and micronutrient availability regulate a somatic mitochondrial quality control pathway via short-chain fatty acid metabolism

Reproductive status, such as pregnancy and menopause in women, profoundly influences metabolism of the body. Mitochondria likely orchestrate many of these metabolic changes. However, the influence of reproductive status on somatic mitochondria and the underlying mechanisms remain largely unexplored. We demonstrate that reproductive signals modulate mitochondria in the Caenorhabditis elegans soma. We show that the germline acts via an RNA endonuclease, HOE-1, which despite its housekeeping role in tRNA maturation, selectively regulates the mitochondrial unfolded protein response (UPRmt). Mechanistically, we uncover a fatty acid metabolism pathway acting upstream of HOE-1 to convey germline status. Furthermore, we link vitamin B12s dietary intake to the germlines regulatory impact on HOE-1-driven UPRmt. Combined, our study uncovers a germline-somatic mitochondrial connection, reveals the underlying mechanism, and highlights the importance of micronutrients in modulating this connection. Our findings provide insights into the interplay between reproductive biology and metabolic regulation.

cell biology↗

A pro-inflammatory stem cell niche drives myelofibrosis through a targetable galectin 1 axis

Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. The majority of patients present with early-stage disease, but a substantial proportion progress to myelofibrosis and/or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and we lack therapies that reliably prevent or reverse fibrosis development. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the crosstalk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a quartet of immune and stromal cell lineages - with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells and pro-inflammatory fibroblasts. We identified the y-galactoside binding protein galectin 1 as a striking biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts, and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival following galectin 1 inhibition. In human bone marrow organoids, TNF increased galectin 1 expression, suggesting a feedback loop wherein the pro-inflammatory MPN clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a valuable resource for studying hematopoietic cell-niche interactions, with broad relevance for cancer-associated inflammation and disorders of tissue fibrosis.

cancer biology↗