Biology subjects

Toivola, D. M.

Publications and source records attributed to Toivola, D. M..

6 recordsLinked to original sources

bioRxiv2026

Lamin A/C regulates the compartment-specific contributions of immune and stromal cells to intestinal inflammation and colitis-associated colon cancer

Inflammatory bowel disease (IBD) arises from dysregulated crosstalk between innate immune, adaptive immune, and stromal compartments, yet the compartment-specific mechanisms driving tissue injury and tumorigenesis remain incompletely defined. To address this gap, we used conditional knockout and overexpression mouse models together with human IBD biopsy analysis to dissect the compartment-specific roles of lamin A/C in intestinal inflammation and colitis-associated tumorigenesis. Pan-hematopoietic lamin A/C deletion attenuated acute dextran sulfate sodium (DSS)-induced colitis. Myeloid-specific lamin A/C deletion ameliorated chronic colitis and was associated with altered dendritic cell (DC) programs, enhanced regulatory T cell (Treg) responses, and reduced effector T cell activation. Adoptive transfer of lamin A/C-deficient bone marrow-derived DCs recapitulated this reduced-damage phenotype in DSS colitis, while proteomic profiling revealed reduced antigen-processing and inflammatory programs together with enhanced metabolic and mucosal defense pathways. T cell-specific lamin A/C deletion reduced the Th1/Treg ratio and limited tumor development by suppressing chronic inflammation, whereas T cell-specific lamin A/C overexpression promoted severe Th1-skewed pathology, sustained intestinal inflammation, and increased colitis-associated tumor burden. Stromal fibroblast-specific lamin A/C deletion generated a tissue-protective niche characterized by enhanced epithelial barrier gene expression, regulatory cytokine production, and remodeling of the local immune milieu. Human IBD biopsies revealed compartment-specific lamin A/C alterations consistent with the murine findings. In lamina propria CD3 T cells, lamin A/C levels were blunted in IBD and associated with local histological severity rather than IBD diagnosis, whereas epithelial lamin A/C showed a steeper crypt-axis spatial gradient in a Crohns disease-specific pattern. Together, these findings identify lamin A/C as a cell-type- and context-dependent regulator of intestinal inflammation and tumorigenesis.

immunology↗

bioRxiv2026

Scinderin-driven Golgi Actin Remodeling coordinates GLP-1 and insulin secretion to regulate glucose homeostasis

Maintenance of glucose homeostasis requires coordinated hormone secretion from intestinal enteroendocrine cells and pancreatic {beta}-cells, yet the intracellular mechanisms that couple nutrient sensing to endocrine output remain poorly defined. Here, we identify the actin remodeler Scinderin (SCIN) as a shared regulator of hormone secretion across these systems. SCIN is selectively expressed in enteroendocrine L-cells and pancreatic {beta}-cells, where it localizes to phosphatidylinositol-4-phosphate (PI(4)P)-enriched Golgi membranes and controls Golgi-associated actin dynamics. Loss of SCIN disrupts Golgi organization, impairs prohormone trafficking, and reduces secretory granule formation, resulting in defective nutrient-stimulated GLP-1 and insulin secretion while preserving cAMP-dependent amplification pathways. In vivo, tissue-specific deletion of Scin compromises incretin responses, {beta}-cell insulin secretion, and systemic glucose homeostasis. Consistent with these findings, SCIN expression is reduced in human diabetic {beta}-cells and associates with stress-related loss of {beta}-cell maturity. Transcriptomic analyses reveal a conserved Golgi stress program upon SCIN loss, linking intracellular trafficking defects to endocrine dysfunction. Together, our results identify SCIN-dependent Golgi actin remodeling as a rate-limiting intracellular mechanism coordinating enteroendocrine and pancreatic hormone secretion. This work uncovers a shared, targetable node controlling endocrine output, providing a mechanistic link between secretory pathway dysfunction and diabetes.

cell biology↗

bioRxiv2026

Keratin 7 protein presence in stool is indicative of active pediatric-onset inflammatory bowel disease

BackgroundInflammatory bowel disease (IBD) is associated with early structural changes in intestinal epithelial cells; however, the associated molecular alterations remain incompletely understood. The cytoskeletal protein keratin (K) 7 was recently found to be focally expressed in the colonic epithelium in IBD, while absent in the healthy colon. Here, we investigated the applicability of K7 as a noninvasive stool biomarker for pediatric IBD. MethodsIn this case-control study including adolescent patients with IBD (n=27) and healthy controls (n=15), stool lysates were analyzed by proteomics, immunoassay and qPCR to determine K7 protein and mRNA content, respectively. Additionally, stool mRNA levels of the simple epithelial keratins, K8, K18, K19 and K20, were measured. ResultsStool proteomic analysis identified focal K7 and K19 in IBD samples. Additionally, 23 differentially abundant proteins, of which 18 were higher in IBD, were identified and Gene Ontology enrichment analysis highlighted immune and inflammatory pathways. K7 specific immunoassay detected fecal K7 protein in all patients with active IBD, including both ulcerative colitis and Crohns disease, while K7 was near or below the detection limit in controls and IBD patients in remission (area under ROC curve=0.88, p<0.0001). While KRT7 mRNA levels were below the detection limit, KRT8 and KRT18 transcripts were elevated in IBD samples compared to controls (p<0.05). ConclusionsK7 protein is elevated in IBD patient stool, reflecting intestinal de novo expression and increased epithelial cell exfoliation. Fecal K7 may provide a novel, noninvasive marker for IBD diagnosis and monitoring.

cell biology↗

bioRxiv2025

Genetically induced mouse model for colon-specific epithelial cell tumorigenesis driven by loss of K8 and Apc

Loss of keratin 8 (K8) has been shown to increase susceptibility towards colonocyte hyperproliferation and tumorigenesis. However, most colorectal cancer (CRC) mouse models require carcinogen, develop small intestinal tumors or have long latency period. The aim was to establish a genetic, colon-specific and more human like CRC model driven by loss of K8 and Apc. Colon epithelium specific targeting using the CDX2P-CreERT2 mice was used to generate K8flox/flox; CDX2P-CreERT2 and K8flox/flox; CDX2P-CreERT2; Apcflox/+ mice. Body weight and stool consistency were monitored, and colon was analyzed for tumor burden and histopathology. Keratin expression, inflammation, and proliferation were assessed using immunoblotting and immunofluorescence analysis. This data was compared to K8 expression analysis in patients with CRC using UALCAN database. K8 downregulation in adult K8flox/flox; CDX2P-CreERT2 mice triggers mild diarrhea and leads to loss of K8 and reduced partner keratin levels in a mosaic pattern in the colonic epithelium, while ileal K8 protein levels are unchanged. K8-negative colon areas display increased crypt loss and more MPO+ cells predominantly in the proximal colon. Increased colonocyte proliferation is observed as increased percentage of Ki67+ cells and lower IL-22BP protein levels throughout the colon. These mice with additional monoallelic Apc inactivation show increased colon tumor formation. In colon adenocarcinoma patients, K8 expression is decreased independent of disease type and stage, age or gender. New genetic and colon-specific mouse model with loss of K8 and Apc adequately resembles human CRC. This study also highlights a role of colonocyte K8 in maintaining colon epithelial integrity and protecting against colon tumorigenesis.

cancer biology↗

bioRxiv2024

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis

Inflammatory bowel disease (IBD) is a debilitating and relapsing chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly (ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, using a biobank IBD patient cohort as well as two mouse models of colitis, i.e., the IBD-mimicking oral dextran sulfate sodium (DSS) exposure model, and the oral Salmonella exposure model. Parp14 was expressed in the human colon, by cells in the lamina propria, but, in particular, by the epithelial cells with a typical granular staining pattern in the cytosol. The same Parp14 staining pattern was evidenced in both colitis models. Body-wide genetic deficiency of Parp14 in C57BL/6N background sensitized mice to DSS colitis. The Parp14-deficient mice displayed increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss and immune cell infiltration. The absence of Parp14 did not affect the mouse colon bacterial microbiota based on PacBio long read sequencing. Also, the colon leukocyte populations of Parp14-deficient mice were normal based on flow cytometry. In contrast, we witnessed an altered transcriptional signature in Parp14-deficient mice with bulk tissue RNA-Seq. Gene Ontology (GO)-based classification of differentially expressed genes demonstrated that the colon transcriptional signature of Parp14-deficient mice was dominated by abnormalities in inflammation and infection responses both prior and after the 1-week DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

immunology↗

bioRxiv2020

Keratins couple with the nuclear lamina and regulate proliferation in colonic epithelial cells

Keratin intermediate filaments (IFs) convey mechanical stability and protection against stress to epithelial cells, and may participate in nuclear structure and organization. Keratins are important for colon health as observed in keratin 8 knockout (K8-/-) mice, which exhibit colonic inflammation and epithelial hyperproliferation. Here, using a full body and two intestinal epithelial-specific K8-/- knockout mouse models, we determine if cytoplasmic keratins affect the nuclear structure and lamina in epithelial colonocytes. K8-/- colonocytes in vivo and in organoid cultures exhibit significantly decreased levels of the major lamins A/C, B1 and B2 in a colon-specific and cell-intrinsic manner independent of major changes in colonic inflammation or microbiota. Downregulation of K8 by siRNA in Caco-2 cells similarly decreases lamin A levels, which recover after re-expression of K8. K8 loss is associated with reduced plectin, LINC complex proteins and lamin-associated proteins, indicating a dysfunctional keratin-nuclear lamina coupling. Immunoprecipitation identifies complexes of colonocyte keratins with the LINC protein SUN2 and lamin A. Hyperphosphorylation of the lamin A-associated cell cycle regulator pRb in K8-/- colonocytes together with increased nuclear localization of the mechanosensor YAP provide a molecular mechanism for the hyperproliferation phenotype. These findings identify a novel, colonocyte-specific role for K8 in nuclear function.

cell biology↗