Biology subjects

Hamm, S.

Publications and source records attributed to Hamm, S..

4 recordsLinked to original sources

bioRxiv2026

Genetic and adenoviral ablation of the choroid plexus reduces postnatal hippocampal neurogenesis

BackgroundChoroid plexus (ChP) produces cerebrospinal fluid (CSF) and regulates brain development and adult subventricular zone (SVZ) neurogenesis, but its role in postnatal hippocampal subgranular zone (SGZ) neurogenesis is not well understood. Neonatal hydrocephalus, a devastating neurological condition characterized by excessive accumulation of CSF in the brain, is sometimes treated in conjunction with partial ChP cauterization in the lateral ventricles, which results in the resolution of clinical symptoms without large reductions in ventricular volumes. To both understand the roles of the ChP/CSF system in normal CNS function and the impact of ChP ablation or cauterization in hydrocephalus, novel tools for the manipulation of CSF volume and production by ChP are urgently needed. MethodsWe first discovered specific "leaky" expression of diphtheria toxin receptors (DTR) in the ChP of adult ROSA26-iDTR mice, which resulted in a robust and permanent ablation of ChP and reduction of ventricular CSF volume after diphtheria toxin (Dtx) administration. In this study, we first tested the effectiveness of this genetic approach for ChP ablation at neonatal ages. We then generated a novel AAV5-CMV-DTR vector with high ChP tropism to more effectively reduce ventricular volume in these neonatal mice. Genetic (ROSA26-iDTR) and gene therapy (AAV5-DTR) approaches were compared for their extent of ChP ablation, reduction of ventricular CSF volume as assessed by MRI, and impact on postnatal hippocampal neurogenesis at neonatal and young adult ages. Lastly, we tested the therapeutic potential of AAV-mediated ChP ablation using an intracisternal kaolin model of hydrocephalus. ResultsIn our genetic model, ChP ablation and CSF volume reduction was robust at postnatal day (P)10-12, but ineffective at P3-5 with standard Dtx dosing (20 ng/g/day for 3 consecutive days). A higher dose of Dtx (40 ng/g/day) at P3-5 generated a mild reduction of CSF volume but was associated with higher subsequent neonatal mortality. In contrast, AAV5 CMV-DTR virus shows high tropism for ChP epithelial cells and leads to near-complete loss of ventricular CSF in neonates. ChP/CSF loss in neonates or young adult mice leads to a substantial reduction of DCX+ cells within the SVZ, but only a moderate reduction of DCX+ neuroblasts in the SGZ, without altering the number of proliferating or apoptotic cells. In the cisternal kaolin model of hydrocephalus, AAV-mediated ChP ablation within 10 hrs after the onset of hydrocephalus profoundly reduced parenchymal edema and corpus callosum hyperintensity without causing ventricular collapse. ConclusionsThis study reports a novel role of the ChP/CSF in maintaining the neuroblast pool in the neurogenic niches in both early postnatal and adult stages. ROSA26-iDTR-mediated ChP ablation is inefficient before P10, suggesting that this mouse line may be of limited utility in the early postnatal period. In contrast, our novel AAV vector efficiently targets the ChP and CSF production at both neonatal and adult ages, and demonstrates the therapeutic potential of AAV-mediated ChP ablation for the treatment of hydrocephalus. The limited radiographic changes in the kaolin mouse model mirror the clinical findings following choroid plexus cauterization in humans.

neuroscience↗

bioRxiv2025

The adhesion molecules β7 integrin and L-selectin contribute to cholestatic liver disease in male mice

Background & AimsPrimary sclerosing cholangitis (PSC) is a long-term progressive disease, often occurring in conjunction with inflammatory bowel disease (IBD). Dysregulated immune cell migration and gut microbiota alterations are implicated in disease progression. Livers of PSC patients show upregulation of the endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1). Here we examined the role of the leukocytic adhesion molecules (AM) {beta}7 integrin and L-selectin, both binding partners of MAdCAM-1, in an experimental mouse model resembling aspects of human PSC. MethodsWild type (WT), {beta}7 integrin-deficient ({beta}7-/-), L-selectin-deficient (L-sel-/-), and L-selectin/{beta}7 integrin double-deficient (L-sel-/-/{beta}7-/-) male mice were compared in the model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy. The extent of pathology was evaluated by serum parameters, histology, flow cytometry, and expression of inflammatory mediators. Fecal microbiota changes were assessed by 16S rRNA amplicon sequencing and intestinal permeability was measured by FITC-dextran assay. ResultsAM-deficient mice were markedly protected from DDC-induced cholangiopathy. Hepatic immune cell populations of AM-deficient mice differed significantly from those of WT mice. Adoptively transferred {beta}7-/- CD8+ T cells caused significantly less liver damage than CD8+ WT T cells in DDC-treated {beta}7-/- mice. DDC-feeding caused substantial changes in fecal microbiota profiles, which differed between the mouse strains, and a strong increase in intestinal permeability that was significantly lower in {beta}7-/- than WT mice. Conclusions{beta}7 integrin and L-selectin contribute to DDC-induced cholangiopathy with {beta}7 integrin-expressing CD8+ T cells playing a crucial role in promoting pathogenesis. In addition, AM-expressing immune cells may contribute to the inflammatory process by causing unfavorable gut microbiota shifts and destabilizing the gut barrier. Synopsis{beta}7 integrin- and/or L-selectin-deficient mice are less susceptible to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced experimental cholangiopathy. {beta}7 integrin-expressing CD8+ T cells contribute to DDC-induced pathogenesis. {beta}7 integrin promotes DDC-induced gut barrier dysfunction and microbiota shifts, potentially exacerbating hepatic injury.

immunology↗

bioRxiv2025

Intercellular adhesion molecule-1 protects against adipose tissue inflammation and insulin resistance but promotes liver inflammation and hepatic fibrosis in mice

Metabolic dysfunction associated steatotic liver disease (MASLD) presents a growing global health problem with a range of manifestations, including steatosis, steatohepatitis, and cirrhosis. It is strongly associated with obesity, disease progression being promoted not only by hepatic leukocyte accumulation but also by inflammatory signals from adipose tissue and an altered gut microbiome. To determine the contribution of intercellular adhesion molecule-1 (ICAM-1) to MASLD pathogenesis, mice with an ICAM-1 mutation (Icam1tmBay) were compared to wild type (WT) mice in a Western-style diet (WD) model. WD-induced MASLD was accompanied by increased ICAM-1 expression in liver, epididymal white adipose tissue (EWAT), and intestine in WT mice. WD-fed Icam1tmBay mice exhibited increased circulating neutrophils, higher frequencies of inflammatory leukocytes in EWAT, and a worsened glucose tolerance when compared to WT mice. In contrast, the mutation resulted in reduced WD-induced liver damage and less accumulation of intrahepatic leukocytes. WD-feeding caused substantial changes in fecal microbiota with decreased microbial diversity that differed between the mouse strains. In conclusion, ICAM-1 positively regulates adipose tissue homeostasis and protects from insulin resistance but promotes liver damage in diet-induced obesity. This points to various organ-specific roles for ICAM-1 and the potential of liver-specific targeting of ICAM-1 for treatment of MASLD.

immunology↗

bioRxiv2021

Casein kinase 1D encodes a novel drug target in Hedgehog-GLI driven cancers and tumor-initiating cells resistant to SMO inhibition

(1) BackgroundAberrant activation of the Hedgehog (HH)/GLI pathway in stem-like tumor initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector Smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH/GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH/GLI driven malignancies. (2) MethodsWe genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity and monitored oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) ResultsWe show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO-inhibitor sensitive and resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent tumor-initiating cancer cells in vitro and in vivo. (4) ConclusionsPharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor sensitive and resistant tumors.

cancer biology↗