Abstract Background and Aims Biliary atresia is a severe inflammatory fibrosing cholangiopathy of neonates unknown etiology. The onset cholestasis at birth implies prenatal liver dysfunction. Our aim was to investigate the mechanisms linked abnormal cholangiocyte development. Approach Results We generated biliary organoids from biopsies infants with normal diseased controls. Organoids emerged livers controls grew as lumen‐containing spheres an epithelial lining cytokeratin‐19 pos albumin neg...

Abstract The cross talk between extrinsic niche-derived and intrinsic hematopoietic stem cell (HSC) factors controlling HSC maintenance remains elusive. Here, we demonstrated that amphiregulin (AREG) from bone marrow (BM) leptin receptor (LepR+) niche cells is an important factor mediates the BM HSCs in maintenance. Mice deficient of DNA repair gene Brca2, specifically LepR+ (LepR-Cre;Brca2fl/fl), exhibited increased frequencies total myeloid-biased HSCs. Furthermore, LepR-Cre;Brca2fl/fl...

Abstract Fanconi anemia (FA) is an inherited bone marrow (BM) failure syndrome, presumably resulting from defects in hematopoietic stem cells (HSCs). Normal HSCs depend more on glycolysis than oxidative phosphorylation (OXPHOS) for energy production. Here, we show that FA are sensitive to the respiration inhibitor NaN3 treatment glycolytic 2-deoxy-d-glucose (2-DG), indicating dependence OXPHOS. undergo glycolysis-to-OXPHOS switch response stress through a p53-dependent mechanism. Metabolic...

Summary The bone marrow ( BM ) microenvironment (niche) plays important roles in supporting normal/abnormal haematopoiesis. We investigated the interaction between leukaemic mesenchymal niche and haematopoietic stem progenitor cells HSPC s) using model of Fanconi anaemia FA ), a genetic disorder characterized by failure leukaemia. Healthy donor s co‐cultured on stromal MSC derived from patients with acute myeloid leukaemia AML exhibited higher human engraftment expansion Non‐obese diabetic...

Abstract Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, variable congenital malformations and predisposition to malignancies. FANCB (also known as FAAP95 ), the only X-linked FA gene discovered thus far. In present study, we investigated hematopoiesis in adult Fancb deficient ( −/y ) mice found that have decreased hematopoietic stem cell (HSC) quiescence accompanied reduced progenitor activity vitro repopulating capacity vivo . Like other mouse models...

Hematopoietic stem cell (HSC) defects can cause repopulating impairment leading to hematologic diseases. To target HSC deficiency in a disease setting, we exploited the defect of Fanconi anemia (FA) HSCs conduct an vivo short hairpin RNA (shRNA) screen. We exposed Fancd2-/- lentiviral shRNA library targeting 947 genes. found enrichment shRNAs genes involved PPARγ pathway that has not been linked homeostasis. inhibition by or chemical compounds significantly improves ability HSCs. Conversely,...

The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient HR. Here we show that PARP1 activation hematopoietic stem progenitor cells (HSPCs) response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, controls the balance between HR non-homologous...

Abstract Hematopoietic stem cells (HSCs) can either self-renew or differentiate into various types of the blood lineage. Signaling pathways that regulate this choice self-renewal versus differentiation are currently under extensive investigation. In study, we report deregulation Notch signaling skews HSC in mouse models Fanconi anemia (FA), a genetic disorder associated with bone marrow failure and progression to leukemia other cancers. mice expressing transgenic reporter, deletion Fanca...

Abstract Fanconi anemia (FA) patients develop bone marrow (BM) failure or leukemia. One standard care for these devastating complications is hematopoietic stem cell transplantation. We identified a group of mesenchymal stromal cells (MSCs)-derived metabolites, glycerophospholipids, and their endogenous inhibitor, 5-(tetradecyloxy)−2-furoic acid (TOFA), as regulators donor progenitor cells. provided two pieces evidence that TOFA could improve hematopoiesis-supporting function FA MSCs: (a)...

// Wei Du 1, 2 , Surya Amarachintha 1 Ozlem Erden Andrew Wilson Qishen Pang 3 Division of Experimental Hematology and Cancer Biology, Cincinnati, 45229 Ohio, USA Divisions Radiation Health,College Pharmacy, UAMS, Little Rock, 72205 Arkansas, Department Pediatrics, University Cincinnati College Medicine, Correspondence to: Pang, email: Qishen.pang@cchmc.org Du, wdu@uams.edu Keywords: fanconi anemia, hematopoietic stem progenitor cells, oncogenic stress, protein arginine methyltransferase 5...

The guanylate cyclase C (GC-C) receptor regulates electrolyte and water secretion into the gut following activation by E. coli enterotoxin STa, or weaker endogenous agonists guanylin uroguanylin. Our previous work has demonstrated that GC-C plays an important role in controlling initial infection as well carrying load of non-invasive bacterial pathogens gut. Here, we use Salmonella enterica serovar Typhimurium to determine whether signaling is host defense against actively invade...

Oxidative stress is considered as an important pathogenic factor in many human diseases including Fanconi anemia (FA), inherited bone marrow failure syndrome with extremely high risk of leukemic transformation. Members the FA protein family are involved DNA damage and other cellular responses. Loss proteins renders cells hypersensitive to oxidative cancer However, how respond remains unclear. By using vivo stress-response mouse strain expressing Gadd45β-luciferase transgene, we show here...

Fanconi anemia (FA) is characterized by a progressive bone marrow failure and an increased incidence of cancer. FA patients have high susceptibility to immune-related complications such as infection posttransplant graft-versus-host disease. In this study, we investigated the effect deficiency in B cell function using Fancc mouse model. Fancc(-/-) cells show specific defect IgG2a switch impaired Ab-secreting (ASC) differentiation. Global transcriptome analysis naive mRNA sequencing...

The etiology and mechanisms for inflammatory bowel disease (IBD) are incompletely known. Determination of new, clinically important intestinal inflammation is imperative developing effective therapies to treat IBD. We sought define a widespread mechanism colon mucosal via the activation TGF-β activated Kinase 1 (TAK1), central regulator cellular actions. Activation TAK1 downstream signaling mediators was determined in pediatric patients with ulcerative colitis (UC) or Crohn's (CD) as well...

Polymeric immunoglobulin receptor (pIgR) transport of secretory A (SIgA) to mucosal surfaces is thought promote gut integrity and immunity Salmonella enterica serovar Typhimurium (S. Typhimurium), an invasive pathogen in mice. To elucidate potential mechanisms, we assessed intestinal barrier function both oral systemic S. virulence pIgR knockout (KO) wildtype (WT) mice.In uninfected animals, harvested jejunal segments for Ussing chamber analyses transepithelial resistance (TER); mesenteric...

Mid-range inhomogeneity or MRI is the significant enrichment of particular nucleotides in genomic sequences extending from 30 up to several thousands nucleotides. The best-known manifestation CpG islands representing CG-rich regions. Recently it was demonstrated that could be observed not only for G+C content but also all other nucleotide pairings (e.g. A+G and G+T) as well individual bases. Various types regions are 4-20 times enriched mammalian genomes compared their occurrences random...

Functional maintenance of hematopoietic stem cells (HSCs) is constantly challenged by stresses like DNA damage and oxidative stress. Foxo factors, particularly Foxo3a, function to regulate the self-renewal HSCs contribute HSC pool during aging providing resistance Fancd2-deficient mice had multiple defects, including loss in early development response cellular The mechanisms underlying include abnormal cell cycle status, quiescence, compromised repopulating capacity HSCs. To address on a...

Abstract Type 1 regulatory T cells (Tr1) are a unique population of CD4+ Foxp3− that express high levels IL-10, and have been defined based on their expression CD49b LAG-3. Despite the critical roles played by Tr1 in controlling cell responses autoimmunity infection, mechanisms underlying homeostasis remain unclear. Here, we investigated homeostasis, phenotype function with age. We found accumulated dramatically Further, produced more IL-10 per compared to Foxp3+ Treg. While aged expressed...

Bone Marrow Hematopoietic Stem Cells (HSCs) require bone marrow microenvironment for their maintenance and proliferation. Culture of Mesenchymal Stromal (MSCs) provides appropriate environmental signals HSCs survival