Winer, D. | Search bioRxiv

bioRxiv2025

Wheat fiber-induced peripheral regulatory T-cells suppress development of colitis

Reduced dietary fiber intake is associated with, and may have contributed to, the post-mid-20th century increase in immune-mediated chronic inflammatory diseases, including inflammatory bowel disease. Reduced fiber intake has resulted, in part, from highly refined foods. For example, modern methods of producing bread removes much of the fiber naturally present in wheat kernels. Accordingly, we hypothesized that wheat fiber might protect against chronic inflammatory diseases. We tested this notion in a murine T-cell transfer colitis model. Rag1-/- mice were fed open-source low-fiber diets enriched, or not with wheat fiber (WF) and then administered CD45Rbhi T-cells. WF conferred robust protection in this colitis model as assessed by an array of clinical, histopathologic, morphologic, and immune-related parameters. WFs protection against colitis associated with a microbiota-dependent increase in Foxp3+ T-cell (Tregs), which could be recapitulated in vitro. WF did not induce Tregs in CNS1-/- mice nor did WF protect against T cell transfer colitis driven by transplant of colitogenic T-cells from CNS1-/- mice. Thus, enriching diet with WF has potential to promote microbiota-dependent peripheral Treg development and, consequently, protect against chronic inflammatory diseases.

immunology↗

bioRxiv2024

Substrate Stiffness Dictates Unique Doxorubicin-induced Senescence-associated Secretory Phenotypes and Transcriptomic Signatures in Human Pulmonary Fibroblasts

Cells are subjected to dynamic mechanical environments which impart forces and induce cellular responses. In age-related conditions like pulmonary fibrosis, there is both an increase in tissue stiffness and an accumulation of senescent cells. While senescent cells produce a senescence-associated secretory phenotype (SASP), the impact of physical stimuli on both cellular senescence and the SASP is not well understood. Here, we show that mechanical tension, modeled using cell culture substrate rigidity, influences senescent cell markers like SA-{beta}-gal and secretory phenotypes. Comparing human primary pulmonary fibroblasts (IMR-90) cultured on physiological (2 kPa), fibrotic (50 kPa), and plastic (approximately 3 GPa) substrates, followed by senescence induction using doxorubicin, we identified unique high-stiffness-driven secretory protein profiles using mass spectrometry and transcriptomic signatures, both showing an enrichment in collagen proteins. Consistently, clusters of p21+ cells are seen in fibrotic regions of bleomycin induced pulmonary fibrosis in mice. Computational meta-analysis of single-cell RNA sequencing datasets from human interstitial lung disease confirmed these stiffness SASP genes are highly expressed in disease fibroblasts and strongly correlate with mechanotransduction and senescence-related pathways. Thus, mechanical forces shape cell senescence and their secretory phenotypes.

cell biology↗