Biology subjects

Shyu, P. T.

Publications and source records attributed to Shyu, P. T..

3 recordsLinked to original sources

bioRxiv2024

Inflammation perturbs hematopoiesis by remodeling specific compartments of the bone marrow niche

Hematopoietic stem and progenitor cells (HSPC) are regulated by interactions with stromal cells in the bone marrow (BM) cavity, which can be segregated into two spatially defined central marrow (CM) and endosteal (Endo) compartments. However, the importance of this spatial compartmentalization for BM responses to inflammation and neoplasia remains largely unknown. Here, we extensively validate a combination of scRNA-seq profiling and matching flow cytometry isolation that reproducibly identifies 7 key CM and Endo populations across mouse strains and accurately surveys both niche locations. We demonstrate that different perturbations exert specific effects on different compartments, with type I interferon responses causing CM mesenchymal stromal cells to adopt an inflammatory phenotype associated with overproduction of chemokines modulating local monocyte dynamics in the surrounding microenvironment. Our results provide a comprehensive method for molecular and functional stromal characterization and highlight the importance of altered stomal cell activity in regulating hematopoietic responses to inflammatory challenges.

cell biology↗

bioRxiv2024

New Insights into Neuromuscular Contracture Reveals Myotendinous- SMAD4 Signaling Underlies Contracture Formation

Neuromuscular contractures (NC) are a prevalent cause of joint deformity in children suffering from neuromuscular disorders or nerve damage, leading to persistent disability. The role of tendon in the development of NC remains poorly understood, with current treatments predominantly targeting muscle. Here, we establish a surgical model of NC in the hindlimb that recapitulates functional deformity and transcriptomic changes observed in human disease. Our findings indicate that in NC, tendons dramatically elongate, undergoing changes in matrix and structural composition that reduce tensile stiffness. Contrary to expectations, we find that tendon elongation was principally driven by increased myotendon infiltration into muscle which restricted muscle elongation contributing to NC. Using lineage tracing, we show that myotendon elongation was due to increased infiltration of intrinsically derived tenocytes. Transcriptional profiling revealed BMP signaling as a key factor in myotendon elongation, corroborated by elevated myotendinous Smad4 activity in both our mouse model and in human NC tissues. Crucially, administration of a small molecule inhibitor of BMP-mediated Smad4 signaling not only restored joint mobility but also prevented myotendon elongation. These insights establish of a clinically relevant mouse model of NC and unveil a novel role for myotendon elongation in NC progression. Excitingly, our results suggest that targeting myotendon signaling could represent a new direction for tendon-focused therapies in NC management.

molecular biology↗

bioRxiv2017

Lipid perturbation compromises UPR-mediated ER homeostasis as a result of premature degradation of membrane proteins

BackgroundPhospholipid homeostasis in biological membranes is essential to maintain functions of organelles such as the endoplasmic reticulum. Phospholipid perturbation has been associated to non-alcoholic fatty liver disease, obesity and other metabolic disorders. However, in most cases, the biological significance of lipid disequilibrium remains unclear. Previously, we reported that Saccharomyces cerevisiae adapts to lipid disequilibrium by upregulating several protein quality control pathways such as the endoplasmic reticulum-associated degradation (ERAD) pathway and the unfolded protein response (UPR).\n\nResultsSurprisingly, we observed certain ER-resident transmembrane proteins (TPs), which form part of the UPR programme, to be destabilised under lipid perturbation (LP). Among these, Sbh1 was prematurely degraded by fatty acid remodelling and membrane stiffening of the ER. Moreover, the protein translocon subunit Sbh1 is targeted for degradation through its transmembrane domain in an unconventional Doa10-dependent manner.\n\nConclusionPremature removal of key ER-resident TPs might be an underlying cause of chronic ER stress in metabolic disorders.

cell biology↗