DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport.

The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport

The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature

WNThigh colon cancer stem cells drive résistance to standard anti-angiogenic therapies

Although chemotherapy combined with the anti-angiogenic, VEGF-blocking antibody bevacizumab is a first-line treatment for metastatic colorectal cancer (CRC) it provides only a modest survival benefit. In this work, we examined potential mechanisms driving bevacizumab resistance in tumors with high levels of Wnt signaling (Wnthi), which make up 37% of CRC cases. We showed that both normal and transformed intestinal stem cells are localized in normoxic zones surrounded by a stable vasculature, while more differentiated intestinal cells are hypoxic and associated with actively sprouting and angiogenic blood vessels. Furthermore, while anti-Vegf treatment efficiently prunes such sprouting blood vessels in Wnthi tumors, stem cell-associated vessels are highly resistant to Vegf deprivation. Analysis of tumors from colon cancer patients confirmed that vessels in WNThi tumors were anti-correlated with active VEGF-signaling. Finally, assessment of transcriptomes from endothelial cell sorted after epithelial activation of Wnt signaling demonstrated increased expression of Sema3F and Apelin. Overexpression of either gene in MC38 cancer cells, normally highly sensitive to Vegfa blockade, switched tumor sensitivity towards resistance. Our work suggests that CRC stem cells actively remodel blood vessels and identifies one of the mechanisms for intrinsic or acquired resistance to anti-VEGF therapies in CRC. Additional studies would enable the development of novel treatments and potential diagnostic tools. Indeed, high WNT activity might represent a negative predictive marker of bevacizumab response. -- Dans 20% des cas de cancer colorectaux (CCR), des métastases sont déjà présentes et justifient un traitement par bevacizumab, un anticorps bloquant le VEGF-A. Ce médicament n’augmente cependant que modestement la survie globale des patients. Nous avons investigué les mécanismes potentiels de résistance au bevacizumab dans des modèles de CCR où la voie de signalisation Wnt est fortement activée (Wnthi) et qui représente 37% des cas. Nous avons observé que les cellules souches intestinales ou cancéreuses sont associées à une vascularisation peu dense et un environnement normoxique. Par contre, les cellules intestinales ou cancéreuses bien différenciées sont hypoxiques et proches de vaisseaux en constant remaniement et fortement angiogéniques. Après traitement par anti- Vegf, la présence de cellules souches rendait les vaisseaux sanguins résistants, annulant ainsi l’effet global sur la croissance tumorale. Ces résultats ont été confirmés dans des échantillons de patients. L’analyse transcriptomique de cellules endothéliales isolées après l’activation épithéliale de la voie Wnt dans l’intestin a démontré que l’expression de Sema3F et Apelin étaient fortement augmentées. La surexpression de Sema3F et Apelin dans des tumeurs MC38 préalablement sensibles aux anti-Vegf a induit un mécanisme de résistance au traitement. Ce travail suggère donc que les cellules souches cancéreuses dans le CCR régulent activement le développement des vaisseaux sanguins et représentent un des mécanismes de résistance aux thérapies anti-angiogéniques. Il propose d’utiliser la signature WNT comme biomarqueur prédictif pour ce type de traitement

Severe Late-Onset Drug-Induced Immune Thrombocytopenia Following IFN β-1a Treatment: A Case Report of a 52-Year-Old Woman with Relapse-Remitting Multiple Sclerosis

Interferon β-1a (IFNβ1a) is considered safe in relapsing-remitting multiple sclerosis (RRMS). Drug-induced thrombocytopenia (DITP) is a rare but underreported adverse event that is often confused with other causes of thrombocytopenia. We report the case of a 52-year-old woman who developed limb and oral mucosa petechiae and hematochezia, 10 years after beginning IFNβ1a. Blood work showed an isolated severe thrombocytopenia and ruled out other autoimmune diseases, viral infections, intravascular hemolysis, and renal impairment. Oral corticosteroids and tranexamic acid were initiated with a favorable platelet response. IFNβ1a was resumed, leading to recurrence of thrombocytopenia. Platelets came back to normal after intravenous immunoglobulins and IFNβ1a was definitively discontinued. To our knowledge, this is the first case of drug-induced immune thrombocytopenia (DITP) associated with IFNβ1a