Biology subjects

Scheers, I.

Publications and source records attributed to Scheers, I..

3 recordsLinked to original sources

bioRxiv2026

Developmental switch dichotomizes kidney response to NPHP3 inactivation and treatment outcome

Nephronophthisis (NPH) is n rare recessive kidney disease caused by biallelic variants in more than 25 NPHP genes encoding proteins that localize to primary cilia. It is characterized by three different forms depending on the age of onset and kidney lesions: infantile (cystic), juvenile/late onset (fibrotic). To date, the pathways linking altered primary cilia function to progressive kidney scarring in NPH remain poorly defined and therapeutic options are lacking. To address these questions, we generated two new mouse NPH models by inactivating Nphp3 specifically in kidney tubules either during embryogenesis or in adult, recapitulating the infantile and juvenile forms of the disease, respectively. Embryonic inactivation produced a rapid and severe cystic phenotype with tubular dedifferentiation, progressive interstitial fibrosis, inflammation and kidney failure, while postnatal inactivation led to a slowly progressive tubulointerstitial nephropathy characterized by tubular atrophy, fibrosis and immune cell infiltration without cyst formation. Strikingly, cilia were preserved in the early stages of both models, indicating that ciliogenesis impairment is not a primary driver of NPH3 pathogenesis. Transcriptomic profiling of the juvenile model revealed that disease initiation is driven by mitochondrial dysfunction, innate immune activation and aberrant cell cycle progression, while epithelial-to-mesenchymal transition and Wnt/{beta}-catenin remodelling emerges only at later stages of disease progression. Therapeutic intervention with the PGE1 (alprostadil) failed to rescue the cystic/infantile model but significantly attenuated fibrosis, inflammation and interstitial fibrosis in the fibrotic/juvenile model. The ability to recapitulate both disease forms through temporal modulation of gene inactivation suggests that primary cilia serve distinct, stage-specific functions in kidney tubular homeostasis, with different cellular processes being selectively vulnerable depending on the causative gene or variant. Collectively, these findings uncover early pathogenic mechanisms that may constitute tractable therapeutic targets for the treatment of nephronophthisis.

pathology↗

bioRxiv2026

Ciliogenic pancreatopathy reveals a link between ciliopathies and exocrine pancreatic disease

BackgroundWhile pancreatic cysts have been described in syndromic ciliopathies, the pancreas is not commonly recognized as a target organ. However, several ciliary gene knockout mouse models develop a pancreatic phenotype combining acinar atrophy and adipocyte accumulation, hereby called adipopancreatosis, suggesting a link between ciliary dysfunction and pancreatic disease. ObjectiveWe investigated whether mutations in ciliopathy-associated genes are linked to pancreatic dysfunction in humans. DesignWe analyzed a cohort of 341 patients with pediatric-onset pancreatic anomalies and characterized the pancreatic phenotype of new mouse models with conditional Nphp3 inactivation or bearing Nphp3 mutations recapitulating human mutations. In patients, pancreatic fat content was quantified using Dixon-MRI. ResultsMutations in the cilium-related HNF1B and NPHP3 were identified in patients presenting with both renal and pancreatic dysfunction. Nphp3 mutant mice developed acinar atrophy, adipopancreatosis, and moderate inflammation. Adipocytes in the pancreas exhibited a white adipocyte-like profile and likely originated from mesothelial-derived fibroblasts. Reduced numbers and altered length of ductal cilia were monitored. Interestingly, secretory canaliculi, typically unnoticed structures found within and between acinar cells and connected to the acinar lumen, exhibited a microcystic morphology. Consistent with the mouse phenotype, Dixon-MRI revealed significantly increased pancreatic fat content in patients with HNF1B and NPHP3 mutations. ConclusionWe describe a previously unrecognized pancreatic manifestation of ciliopathies, which we name ciliogenic pancreatopathy. Patients with known ciliopathy-causing mutations should be evaluated for this pancreatic condition, particularly those with kidney disease, as concomitant exocrine pancreatic insufficiency may further compromise renal function or the outcome of kidney graft. What is already known on this topicO_LICiliopathies, resulting from defects in primary cilia, are genetic disorders primarily affecting the kidney and liver. C_LIO_LIPancreatic cysts have been sporadically reported in syndromic ciliopathies. C_LIO_LIThe pancreas is not currently recognized as a major target organ of ciliary dysfunction. C_LIO_LIA clear link between ciliary gene mutations and pancreatic anomalies is still unknown. C_LIO_LIAnimal studies have suggested a possible association between ciliary dysfunction and pancreatic anomalies. C_LI What this study addsO_LIIdentifies HNF1B and NPHP3 mutations as genetic causes of a pancreatic phenotype characterized by acinar atrophy and adipose replacement (adipopancreatosis). C_LIO_LIDemonstrates the presence of defective ductal cilia and moderate inflammation in the pancreas of Nphp3 mutant mice. C_LIO_LIReveals that secretory canaliculi in the exocrine pancreas of Nphp3 mutant mice acquire a microcystic morphology. C_LIO_LIShows that patients with HNF1B or NPHP3 mutations have significantly increased pancreatic fat content by Dixon-MRI. C_LIO_LIDefines a new disease entity, ciliogenic pancreatopathy, as a pancreatic manifestation of ciliopathies. C_LI How this study might affect research, practice or policyO_LIEstablishes the pancreas as a novel and clinically relevant target of ciliopathies. C_LIO_LIExpands the phenotypic spectrum of HNF1B- and NPHP3-related diseases to include exocrine pancreatic dysfunction. C_LIO_LISuggests that patients with ciliopathy-causing mutations should be evaluated for exocrine pancreatic insufficiency. C_LIO_LIHighlights the need to consider pancreatic function monitoring in kidney disease and transplant settings. C_LIO_LIOpens new research avenues into the role of primary cilia in pancreatic homeostasis and disease. C_LI

cell biology↗

bioRxiv2025

Human mitochondrial DNA variants influence telomere length: evidence from a transmitochondrial cybrid model

Telomere shortening is a hallmark of aging, yet telomere length (TL) varies considerably among individuals and is strongly influenced by inheritance. In mice, efficient mitochondrial function-characterized by low reactive oxygen species (ROS) production-is critical for telomere elongation during early embryogenesis. Since mitochondrial DNA (mtDNA) encodes several subunits of the electron transport chain, it may influence TL at birth by regulating mitochondrial function in utero. To explore the relationship between mtDNA and TL in human, we used a transmitochondrial cybrid approach, introducing mitochondria from donor platelets with varying telomere lengths into mtDNA-depleted cells. This revealed an inverse correlation between donor blood TL and mitochondrial ROS levels measured in the resulting cybrids, suggesting that specific mtDNA variants may contribute to the maintenance of long telomeres in humans by enhancing mitochondrial fitness. During in vitro cybrid formation, a transient phase of oxidative stress precedes cellular adaptation. In this specific window, mtDNA variants associated with reduced complex I (CI) activity induced rapid telomere shortening--an effect rescued by antioxidant and NAD precursor supplementation. While these variants occur naturally in certain individuals with long telomeres, our data suggest that, at least under in vitro conditions of acute oxidative stress, CI is critical to support PARP1 activity by maintaining the NAD/NADH balance, thereby preserving telomere integrity. Collectively, these findings solidify the link between mtDNA variants and human TL regulation, highlighting potential therapeutic opportunities for mitochondrial replacement strategies. Significance StatementTelomere length at birth influences aging trajectories and disease risk later in life, yet the mechanisms governing this trait remain incompletely understood. Using a transmitochondrial cybrid approach, we show that single-nucleotide variants in the mitochondrial genome of healthy donors directly affect mitochondrial metabolism and reactive oxygen species production. In addition, mitochondrial ROS levels measured in cybrids inversely correlate with blood cell telomere length in donors. During cybrid formation, mitochondrial DNA variants associated with reduced CI activity promote telomere shortening. Attrition was reversed by antioxidant and NAD precursor supplementation, pointing to an essential role for robust CI function in sustaining telomere length during acute oxidative stress, at least under in vitro conditions. Together, these findings establish a direct link between mitochondrial genetics, redox homeostasis, and telomere maintenance in human cells.

cell biology↗