bims-bicyki Biomed News
on Bicaudal-C1 and interactors in cystic kidney disease
Issue of 2021–12–19
nineteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne
  1. Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD.
  2. Arrhythmogenic Hearts in PKD2 Mutant Mice Are Characterized by Cardiac Fibrosis, Systolic, and Diastolic Dysfunctions.
  3. Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD.
  4. Curcumin supplementation in pediatric patients: A systematic review of current clinical evidence.
  5. The Design, Synthesis and Evaluation of Rho-kinase Inhibitory Activity of 4-aryl-thiazole-2-amines.
  6. In vitro differentiation of ciliated cells in ALI-cultured human airway epithelium - The framework for functional studies on airway differentiation in ciliopathies.
  7. Ciliate cortical organization and dynamics for cell motility: Comparing ciliates and vertebrates.
  8. Cross Talk between ARF1 and RhoA Coordinates the Formation of Cytoskeletal Scaffolds during Chlamydia Infection.
  9. The centriolar tubulin code.
  10. Isolation of Fallopian Tube Epithelium for Assessment of Cilia Beating Frequency (CBF).
  11. ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis.
  12. Planar organization of airway epithelial cell morphology using hydrogel grooves during ciliogenesis fails to induce ciliary alignment.
  13. A Rare Cause of Cholestasis Related to Polycystic Liver Disease.
  14. LRRK2 regulates actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.
  15. The Hippo Pathway Effectors YAP and TAZ Regulate LH Release by Pituitary Gonadotrope Cells in Mice.
  16. Cell Cycle Dysregulation and Renal Fibrosis.
  17. Cystic fibrosis associated liver disease in children.
  18. Autosomal dominant tubulointerstitial kidney disease with a novel heterozygous missense mutation in the uromodulin gene: A case report.
  19. N6-methyladenosine (m6A) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells.
  1. Front Med (Lausanne). 2021 ;8 740087
    Metabolic Reprogramming and Reconstruction: Integration of Experimental and Computational Studies to Set the Path Forward in ADPKD.
    Roberto Pagliarini, Christine Podrini.
      Metabolic reprogramming is a key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD) characterized by changes in cellular pathways occurring in response to the pathological cell conditions. In ADPKD, a broad range of dysregulated pathways have been found. The studies supporting alterations in cell metabolism have shown that the metabolic preference for abnormal cystic growth is to utilize aerobic glycolysis, increasing glutamine uptake and reducing oxidative phosphorylation, consequently resulting in ADPKD cells shifting their energy to alternative energetic pathways. The mechanism behind the role of the polycystin proteins and how it leads to disease remains unclear, despite the identification of numerous signaling pathways. The integration of computational data analysis that accompanies experimental findings was pivotal in the identification of metabolic reprogramming in ADPKD. Here, we summarize the important results and argue that their exploitation may give further insights into the regulative mechanisms driving metabolic reprogramming in ADPKD. The aim of this review is to provide a comprehensive overview on metabolic focused studies and potential targets for treatment, and to propose that computational approaches could be instrumental in advancing this field of research.
    Keywords:  ADPKD; drug repositioning; metabolism; systems biology; systems medicine; therapeutics
    DOI:  https://doi.org/10.3389/fmed.2021.740087
  2. Front Cardiovasc Med. 2021 ;8 772961
    Arrhythmogenic Hearts in PKD2 Mutant Mice Are Characterized by Cardiac Fibrosis, Systolic, and Diastolic Dysfunctions.
    Farideh Amirrad, Rajasekharreddy Pala, Kiumars Shamloo, Brian S Muntean, Surya M Nauli.
      Autosomal dominant polycystic kidney disease (PKD) is a hereditary disorder affecting multiple organs, including the heart. PKD has been associated with many cardiac abnormalities including the arrhythmogenic remodeling in clinical evaluations. In our current study, we hypothesized that Pkd2 gene mutation results in structural and functional defects in the myocardium. The structural and functional changes of Pkd2 mutant hearts were analyzed in the myocardial-specific Pkd2 knockout (KO) mouse. We further assessed a potential role of TGF-b1 signaling in the pathology of Pkd2-KO hearts. Hearts from age-matched 6-month-old MyH6•Pkd2 wt/wt (control or wild-type) and MyH6•Pkd2 flox/flox (mutant or Pkd2-KO) mice were used to study differential heart structure and function. Cardiac histology was used to study structure, and the "isolated working heart" system was adapted to mount and perfuse mouse heart to measure different cardiac parameters. We found that macrophage1 (M1) and macrophage 2 (M2) infiltration, transforming growth factor (TGF-b1) and TGF-b1 receptor expressions were significantly higher in Pkd2-KO, compared to wild-type hearts. The increase in the extracellular matrix in Pkd2-KO myocardium led to cardiac hypertrophy, interstitial and conduction system fibrosis, causing cardiac dysfunction with a predisposition to arrhythmia. Left ventricular (LV) expansion or compliance and LV filling were impaired in fibrotic Pkd2-KO hearts, resulted in diastolic dysfunction. LV systolic contractility and elastance decreased in fibrotic Pkd2-KO hearts, resulted in systolic dysfunction. Compared to wild-type hearts, Pkd2-KO hearts were less responsive to the pharmacological stress-test and changes in preload. In conclusion, Pkd2-KO mice had systolic and diastolic dysfunction with arrhythmogenic hearts.
    Keywords:  cardiac function; cardiovascular; fibrosis; inflammation; polycystic kidney disease
    DOI:  https://doi.org/10.3389/fcvm.2021.772961
  3. Clin J Am Soc Nephrol. 2021 Dec 14. pii: CJN.08950621. [Epub ahead of print]
    Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD.
    Kristen Nowak, Heather Farmer-Bailey, Wei Wang, Zhiying You, Cortney Steele, Melissa Cadnapaphornchai, Jelena Klawitter, Nayana Patel, Diana George, Anna Jovanovich, Danielle Soranno, Berenice Gitomer, Michel Chonchol.
      Background and Objectives: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. Design, Setting, Participants, and Measurements: In a randomized, placebo-controlled, double-blind trial, 68 children/ young adults 6-25 years of age with ADPKD and an estimated glomerular filtration rate >80 mL/min/1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight/day) or placebo, administered in powder form for 12 months. The co-primary outcomes were brachial artery flow-mediated dilation [FMDBA] and aortic pulse-wave velocity [aPWV]. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume]) by magnetic resonance imaging. In a sub-group of participants ≥18 years, vascular oxidative stress was measured as the change in FMDBA following an acute infusion of ascorbic acid. Results: Enrolled participants were 18±5 [mean±s.d.] years; 54% female; baseline FMDBA was 9.3±4.1 % change, and baseline aPWV was 512±94 cm/sec. Fifty-seven participants completed the trial. Neither co-primary endpoint changed with curcumin (estimated change [95% confidence interval] for FMDBA (% change): curcumin: 1.14 [-0.84, 3.13]; placebo: 0.33 [-1.34, 2.00]; estimated difference for change: 0.81 [-1.21, 2.84], p=0.48; aPWV (cm/sec: curcumin: 0.6 [-25.7, 26.9]; placebo: 6.5 [-20.4, 33.5]; estimated difference for change: -5.9 [-35.8, 24.0], p=0.67) (intent to treat). There was no curcumin-specific reduction in vascular oxidative stress, nor changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared to placebo. Conclusions: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD.
    DOI:  https://doi.org/10.2215/CJN.08950621
  4. Phytother Res. 2021 Dec 14.
    Curcumin supplementation in pediatric patients: A systematic review of current clinical evidence.
    Zinat Heidari, Maryam Daei, Motahareh Boozari, Tannaz Jamialahmadi, Amirhossein Sahebkar.
      This systematic review was designed to determine the clinical efficacy and safety of curcumin supplementation for pediatric patients based on clinical trials in children. We systematically searched electronic databases including PubMed, EMBASE, Web of Science, and Scopus for all studies that investigated curcumin administration in the pediatric population without any time frame limitation. Finally, we identified 16 studies for this review. Clinical efficacy and safety of curcumin were assessed in children with inflammatory and immune disorders (including asthma, inflammatory bowel disease (IBD), and juvenile idiopathic arthritis (JIA)), metabolic disorders, autosomal dominant polycystic kidney disease (ADPKD), cystic fibrosis (CF), tetralogy of Fallot (TOF), and infectious diseases. Curcumin was administered in a wide range of doses (45 mg-4,000 mg daily) and durations (2-48 weeks). Overall, curcumin was well tolerated in all studies and improved the severity of inflammatory and immune disorders and metabolic diseases. However, more studies are needed to clarify the role of curcumin supplementation among children with ADPKD, CF, TOF, and infectious diseases. Because of substantial heterogeneity in methodological quality, design, outcomes, dose, duration of intake, formulations, and study populations across studies, no quantitative analysis was performed. Additional large-scale, randomized, placebo-controlled clinical trials are needed to confirm the results of the conducted studies.
    Keywords:  clinical trial; curcumin; efficacy; pediatric; safety
    DOI:  https://doi.org/10.1002/ptr.7350
  5. Iran J Pharm Res. 2021 ;20(3): 121-131
    The Design, Synthesis and Evaluation of Rho-kinase Inhibitory Activity of 4-aryl-thiazole-2-amines.
    Linan Wang, Ben Ouyang, Meixia Fan, Junhui Qi, Lei Yao.
      Rho-associated kinases (ROCK) are a class of serine/threonine kinases that play important roles in various biological processes. ROCK are becoming attractive targets for drug designing. A novel scaffold was designed according to molecular hybridization strategy, then a series of 4-aryl-5-aminomethyl-thiazole-2-amines were synthesized, and their inhibitory activities on ROCK were screened by enzyme-linked immunosorbent assay (ELISA). The results showed that 4-aryl-5-aminomethyl-thiazole-2-amines derivatives displayed certain ROCK II inhibitory activities. The IC50 value of the most potent compound 4v was found to be 20 nM. The preliminary structure-activity-relationship investigation showed that compounds with 4-pyridine substitution were generally found to be more potent than compounds with 3-pyridine substitution. The molecular docking studies indicated that more optimization work needs to conduct to obtain more potent ROCK inhibitors.
    Keywords:  4-aryl-thiazole-2-amine; Inhibitors; Kinase; ROCK; Synthesis
    DOI:  https://doi.org/10.22037/ijpr.2020.114468.14866
  6. Eur J Cell Biol. 2021 Dec 02. pii: S0171-9335(21)00040-6. [Epub ahead of print]101(1): 151189
    In vitro differentiation of ciliated cells in ALI-cultured human airway epithelium - The framework for functional studies on airway differentiation in ciliopathies.
    Zuzanna Bukowy-Bieryłło, Patrycja Daca-Roszak, Joanna Jurczak, Hanna Przystałowska-Macioła, Roman Jaksik, Michał Witt, Ewa Ziętkiewicz.
      Primary cultures of the human airway epithelium (AE) cells are an indispensable tool in studies of pathophysiology of genetic and environmental pulmonary diseases, including cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and chronic obstructive pulmonary disease (COPD). Air-liquid interface (ALI) culture is the best method to follow the differentiation of ciliated cells, whose dysfunction forms the basis of PCD. Here, we used custom-designed Taqman Low Density Array (TLDA), qRT-PCR-based assay, to analyze expression of 14 AE genes in cells from healthy donors, cultured in ALI settings using Pneumacult medium, with the focus on genes involved in cilia differentiation and in PCD pathogenesis. The results of TLDA assay were compared with the bulk RNAseq analysis, and placed in the cellular context using immunofluorescent staining (IF) of ALI cultured cells. Expression analysis revealed culture time-related upregulation of the majority of cilia-related genes, followed by the appearance of respective protein signals visualized by IF. Strong correlation of TLDA with RNAseq results indicated that TLDA assay is a reliable and scalable approach to analyze expression of selected genes specific for different AE cell types. Characterization of temporal and inter-donor changes in the expression of these genes, performed in healthy donors and in well-defined ALI/Pnemacult culture conditions, provides a useful reference relevant for a broad spectrum of functional studies where the in vitro AE differentiation is in focus.
    Keywords:  Airway tissue differentiation, genetic disorders, ciliogenesis; Bulk RNAseq; Gene expression; Immunofluorescence; Primary ciliary dyskinesia genes; Protein expression; TLDA; qRT-PCR
    DOI:  https://doi.org/10.1016/j.ejcb.2021.151189
  7. J Eukaryot Microbiol. 2021 Dec 12. e12880
    Ciliate cortical organization and dynamics for cell motility: Comparing ciliates and vertebrates.
    Adam W J Soh, Chad G Pearson.
      The generation of efficient fluid flow is crucial for organismal development and homeostasis, sexual reproduction, and motility. Multi-ciliated cells possess fields of motile cilia that beat in synchrony to propel fluid. Ciliary arrays are remarkably conserved in their organization and function. Ciliates have polarized multi-ciliary arrays (MCAs) to promote fluid flow for cell motility. The ciliate cortex is decorated with hundreds of basal bodies (BB) forming linear rows along the cell's anterior-posterior axis. BBs scaffold and position cilia to form the organized ciliary array. Nascent BBs assemble at the base of BBs. As nascent BBs mature, they integrate into the cortical BB and cytoskeletal network and nucleate their own cilium. The organization of MCAs is balanced between cortical stability and cortical dynamism. The cortical cytoskeletal network both establishes and maintains a stable organization of the MCA in the face of mechanical forces exerted by ciliary beating. At the same time, MCA organization is plastic, such that it remodels for optimal ciliary mobility during development and in response to environmental conditions. Such plasticity promotes effective feeding and ecological behavior required for these organisms. Together, these properties allow an organism to effectively sense, adapt to, and move through its environment.
    Keywords:   Tetrahymena ; Basal body; basal foot; cilia; ciliary rootlet; ciliate; cortex; striated fiber
    DOI:  https://doi.org/10.1111/jeu.12880
  8. mBio. 2021 Dec 14. e0239721
    Cross Talk between ARF1 and RhoA Coordinates the Formation of Cytoskeletal Scaffolds during Chlamydia Infection.
    Adam Haines, Jordan Wesolowski, Nathan M Ryan, Tiago Monteiro-Brás, Fabienne Paumet.
      Chlamydia trachomatis is an obligate intracellular bacterium that has developed sophisticated mechanisms to survive inside its infectious compartment, the inclusion. Notably, Chlamydia weaves an extensive network of microtubules (MTs) and actin filaments to enable interactions with host organelles and enhance its stability. Despite the global health and economic burden caused by this sexually transmitted pathogen, little is known about how actin and MT scaffolds are integrated into an increasingly complex virulence system. Previously, we established that the chlamydial effector InaC interacts with ARF1 to stabilize MTs. We now demonstrate that InaC regulates RhoA to control actin scaffolds. InaC relies on cross talk between ARF1 and RhoA to coordinate MTs and actin, where the presence of RhoA downregulates stable MT scaffolds and ARF1 activation inhibits actin scaffolds. Understanding how Chlamydia hijacks complex networks will help elucidate how this clinically significant pathogen parasitizes its host and reveal novel cellular signaling pathways. IMPORTANCE Chlamydia trachomatis is a major cause of human disease worldwide. The ability of Chlamydia to establish infection and cause disease depends on the maintenance of its parasitic niche, called the inclusion. To accomplish this feat, Chlamydia reorganizes host actin and microtubules around the inclusion membrane. How Chlamydia orchestrates these complex processes, however, is largely unknown. Here, we discovered that the chlamydial effector InaC activates Ras homolog family member A (RhoA) to control the formation of actin scaffolds around the inclusion, an event that is critical for inclusion stability. Furthermore, InaC directs the kinetics of actin and posttranslationally modified microtubule scaffolds by mediating cross talk between the GTPases that control these cytoskeletal elements, RhoA and ADP-ribosylation factor 1 (ARF1). The precise timing of these events is essential for the maintenance of the inclusion. Overall, this study provides the first evidence of ARF1-RhoA-mediated cross talk by a bacterial pathogen to coopt the host cytoskeleton.
    Keywords:  ARF1; Chlamydia; GTPases; RhoA; actin; cytoskeleton; microtubules
    DOI:  https://doi.org/10.1128/mBio.02397-21
  9. Semin Cell Dev Biol. 2021 Dec 09. pii: S1084-9521(21)00309-8. [Epub ahead of print]
    The centriolar tubulin code.
    Paul Guichard, Marine H Laporte, Virginie Hamel.
      Centrioles are microtubule-based cell organelles present in most eukaryotes. They participate in the control of cell division as part of the centrosome, the major microtubule-organizing center of the cell, and are also essential for the formation of primary and motile cilia. During centriole assembly as well as across its lifetime, centriolar tubulin display marks defined by post-translational modifications (PTMs), such as glutamylation or acetylation. To date, the functions of these PTMs at centrioles are not well understood, although pioneering experiments suggest a role in the stability of this organelle. Here, we review the current knowledge regarding PTMs at centrioles with a particular focus on a possible link between these modifications and centriole's architecture, and propose possible hypothesis regarding centriolar tubulin PTMs's function.
    Keywords:  Basal bodies; Centrioles; Cryo-EM; Expansion microscopy; PTMs; Tubulin
    DOI:  https://doi.org/10.1016/j.semcdb.2021.12.001
  10. Methods Mol Biol. 2022 ;2424 179-187
    Isolation of Fallopian Tube Epithelium for Assessment of Cilia Beating Frequency (CBF).
    Angela Russo, Joanna E Burdette.
      The fallopian tube epithelium (FTE) plays a critical role in reproduction and the genesis of ovarian cancer. The FTE columnar cells present with hair-like structures named "cilia" that are required for normal FTE function. Impairment of ciliary motion can lead to infertility, and it is influenced by hormonal signaling and endocrine disrupting compounds. Studying how cilia beating changes in response to these compounds is critical for understanding FTE physiology and pathology. In this protocol, we describe methods for isolating human fallopian tube epithelium, oviduct (murine equivalent of fallopian tube) epithelium, and ovaries. In addition, we describe methods for imaging and measuring cilia beating frequency using high-resolution time-lapse imaging.
    Keywords:  Cilia beating frequency; Fallopian tube epithelium; Ovary; Oviduct; Ovulation
    DOI:  https://doi.org/10.1007/978-1-0716-1956-8_12
  11. JHEP Rep. 2022 Jan;4(1): 100386
    ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis.
    Christina Nalkurthi, Wayne A Schroder, Michelle Melino, Katharine M Irvine, Melanie Nyuydzefe, Wei Chen, Jing Liu, Michele W L Teng, Geoffrey R Hill, Patrick Bertolino, Bruce R Blazar, Gregory C Miller, Andrew D Clouston, Alexandra Zanin-Zhorov, Kelli P A MacDonald.
       Background & Aims: Fibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved in both inflammatory reactions and altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target.
    Methods: We used the thioacetamide-induced liver fibrosis model to examine the efficacy of administration of the selective ROCK2 inhibitor KD025 to prevent or treat liver fibrosis and its impact on immune composition and function.
    Results: Prophylactic and therapeutic administration of KD025 effectively attenuated thioacetamide-induced liver fibrosis and promoted fibrotic regression. KD025 treatment inhibited liver macrophage tumour necrosis factor production and disrupted the macrophage niche within fibrotic septae. ROCK2 targeting in vitro directly regulated macrophage function through disruption of signal transducer and activator of transcription 3 (STAT3)/cofilin signalling pathways leading to the inhibition of pro-inflammatory cytokine production and macrophage migration. In vivo, KDO25 administration significantly reduced STAT3 phosphorylation and cofilin levels in the liver. Additionally, livers exhibited robust downregulation of immune cell infiltrates and diminished levels of retinoic acid receptor-related orphan receptor gamma (RORγt) and B-cell lymphoma 6 (Bcl6) transcription factors that correlated with a significant reduction in liver IL-17, splenic germinal centre numbers and serum IgG.
    Conclusions: As IL-17 and IgG-Fc binding promote pathogenic macrophage differentiation, together our data demonstrate that ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect effects on macrophage function and highlight the therapeutic potential of ROCK2 inhibition in liver fibrosis.
    Lay summary: By using a clinic-ready small-molecule inhibitor, we demonstrate that selective ROCK2 inhibition prevents and reverses hepatic fibrosis through its pleiotropic effects on pro-inflammatory immune cell function. We show that ROCK2 mediates increased IL-17 production, antibody production, and macrophage dysregulation, which together drive fibrogenesis in a model of chemical-induced liver fibrosis. Therefore, in this study, we not only highlight the therapeutic potential of ROCK2 targeting in chronic liver disease but also provide previously undocumented insights into our understanding of cellular and molecular pathways driving the liver fibrosis pathology.
    Keywords:  ALT, alanine aminotransferase; AST, aspartate aminotransferase; B cells; BMDM, bone marrow-derived macrophages; Bcl6, B-cell lymphoma 6; CLD, chronic liver disease; Col1a2, collagen type α1; DR, ductular reaction; ECM, extracellular matrix; GC, germinal centre; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; IHC, immunohistochemical; IL-17; Inflammation; LPS, lipopolysaccharide; Liver fibrosis; MMP, matrix metalloproteinase; Macrophages; NASH, non-alcoholic steatohepatitis; RAR, retinoic acid receptor; ROCK, Rho-associated coiled-coil forming protein kinases; ROCK2; ROCK2, Rho-associated kinase 2; RORγt, RAR-related orphan receptor gamma; SR, Sirius red; STAT3, signal transducer and activator of transcription 3; TAA, thioacetamide; TGF-β, transforming growth factor-beta; TNF, tumour necrosis factor; Tfh, T follicular helper; Th17, T helper 17; Therapy; cGVHD, chronic graft-vs-host disease; pCofilin, phosphorylated cofilin; pMac, peritoneal macrophages; pSTAT3, phosphorylated signal transducer and activator of transcription; qRT-PCR, quantitative real-time PCR; α-SMA, alpha smooth muscle actin
    DOI:  https://doi.org/10.1016/j.jhepr.2021.100386
  12. Biomater Sci. 2021 Dec 13.
    Planar organization of airway epithelial cell morphology using hydrogel grooves during ciliogenesis fails to induce ciliary alignment.
    Ratna Varma, James Poon, Zhongfa Liao, J Stewart Aitchison, Thomas K Waddell, Golnaz Karoubi, Alison P McGuigan.
      Topographical cues are known to influence cell organization both in native tissues and in vitro. In the trachea, the matrix beneath the epithelial lining is composed of collagen fibres that run along the long axis of the airway. Previous studies have shown that grooved topography can induce morphological and cytoskeletal alignment in epithelial cell lines. In the present work we assessed the impact of substrate topography on the organization of primary human tracheal epithelial cells (HTECs) and human induced pluripotent stem cell (hiPSC)-derived airway progenitors and the resulting alignment of cilia after maturation of the airway cells under Air-Liquid-Interface (ALI) culture. Grooves with optimized dimensions were imprinted into collagen vitrigel membranes (CVM) to produce gel inserts for ALI culture. Grooved CVM substrates induced cell alignment in HTECs and hiPSC airway progenitors in submerged culture. Further, both cell types were able to terminally differentiate into a multi-ciliated epithelium on both flat and groove CVM substrates. When exposed to ALI conditions, HTECs lost alignment after 14 days. Meanwhile, hiPSC-derived airway progenitors maintained their alignment throughout 31 days of ALI culture. Interestingly, neither initial alignment on the grooves, nor maintained alignment on the grooves induced alignment of cilia basal bodies, an indication of the direction of ciliary beating direction in the airway cells. Planar organization of airway cells during or prior to ciliogenesis therefore does not appear to be a feasible strategy to control cilia organization and subsequent airway epithelial function and additional cues are likely necessary to produce cilia alignment.
    DOI:  https://doi.org/10.1039/d1bm01327k
  13. GE Port J Gastroenterol. 2021 Nov-Dec;28(6):28(6): 443-445
    A Rare Cause of Cholestasis Related to Polycystic Liver Disease.
    Pedro Costa-Moreira, Susana Lopes, Guilherme Macedo.
      
    Keywords:  Cholestasis; Polycystic liver disease; Vascular liver disease
    DOI:  https://doi.org/10.1159/000514008
  14. J Mol Cell Biol. 2021 Dec 16. pii: mjab079. [Epub ahead of print]
    LRRK2 regulates actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.
    Zhen-Nan Pan, Jing-Cai Liu, Jia-Qian Ju, Yue Wang, Shao-Chen Sun.
      LRRK2 belongs to the Roco GTPase family and is a large multi-domain protein harboring both GTPase and kinase activities. LRRK2 plays indispensable roles in many processes, such as autophagy and vesicle trafficking in mitosis. In the present study, we showed the critical roles of LRRK2 in mammalian oocyte meiosis. LRRK2 is mainly accumulated at the meiotic spindle periphery during oocyte maturation. Depleting LRRK2 led to the polar body extrusion defects and also induced large polar bodies in mouse oocytes. Mass spectrometry analysis and co-immunoprecipitation results showed that LRRK2 was associated with several actin-regulating factors such as Fascin and ROCK, and depletion of LRRK2 affected the expression of ROCK, phosphorylated cofilin, and Fascin. Further analysis showed that LRRK2 depletion did not affect spindle organization but caused the failure of spindle migration, which was largely due to the decrease of cytoplasmic actin filaments. Moreover, LRRK2 showed similar localization pattern with mitochondria, and LRRK2 was associated with several mitochondria-related proteins. Indeed, mitochondrial distribution and function were all disrupted in LRRK2-depleted oocytes. In summary, our results indicated the critical roles of LRRK2 in actin assembly for spindle migration and mitochondrial function in mouse oocyte meiosis.
    Keywords:  LRRK2; actin; meiosis; oocyte; spindle
    DOI:  https://doi.org/10.1093/jmcb/mjab079
  15. Endocrinology. 2022 01 01. pii: bqab238. [Epub ahead of print]163(1):
    The Hippo Pathway Effectors YAP and TAZ Regulate LH Release by Pituitary Gonadotrope Cells in Mice.
    Ariane Lalonde-Larue, Alexandre Boyer, Esdras Corrêa Dos Santos, Derek Boerboom, Daniel J Bernard, Gustavo Zamberlam.
      The Hippo transcriptional coactivators YAP and TAZ exert critical roles in morphogenesis, organ size determination and tumorigenesis in many tissues. Although Hippo kinase cascade activity was recently reported in the anterior pituitary gland in mice, the role of the Hippo effectors in regulating gonadotropin production remains unknown. The objective of this study was therefore to characterize the roles of YAP and TAZ in gonadotropin synthesis and secretion. Using a conditional gene targeting approach (cKO), we found that gonadotrope-specific inactivation of Yap and Taz resulted in increased circulating levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in adult male mice, along with increased testosterone levels and testis weight. Female cKO mice had increased circulating LH (but not FSH) levels, which were associated with a hyperfertility phenotype characterized by higher ovulation rates and larger litter sizes. Unexpectedly, the loss of YAP/TAZ did not appear to affect the expression of gonadotropin subunit genes, yet both basal and GnRH-induced LH secretion were increased in cultured pituitary cells from cKO mice. Likewise, pharmacologic inhibition of YAP binding to the TEAD family of transcription factors increased both basal and GnRH-induced LH secretion in LβT2 gonadotrope-like cells in vitro without affecting Lhb expression. Conversely, mRNA levels of ChgA and SgII, which encode key secretory granule cargo proteins, were decreased following pharmacologic inhibition of YAP/TAZ, suggesting a mechanism whereby YAP/TAZ regulate the LH secretion machinery in gonadotrope cells. Together, these findings represent the first evidence that Hippo signaling may play a role in regulating pituitary LH secretion.
    Keywords:  KO mice; TAZ; YAP; fertility; gonadotropins
    DOI:  https://doi.org/10.1210/endocr/bqab238
  16. Front Cell Dev Biol. 2021 ;9 714320
    Cell Cycle Dysregulation and Renal Fibrosis.
    Yun-Shan Wu, Shan Liang, Dong-Yi Li, Jun-Hao Wen, Ji-Xin Tang, Hua-Feng Liu.
      Precise regulation of cell cycle is essential for tissue homeostasis and development, while cell cycle dysregulation is associated with many human diseases including renal fibrosis, a common process of various chronic kidney diseases progressing to end-stage renal disease. Under normal physiological conditions, most of the renal cells are post-mitotic quiescent cells arrested in the G0 phase of cell cycle and renal cells turnover is very low. Injuries induced by toxins, hypoxia, and metabolic disorders can stimulate renal cells to enter the cell cycle, which is essential for kidney regeneration and renal function restoration. However, more severe or repeated injuries will lead to maladaptive repair, manifesting as cell cycle arrest or overproliferation of renal cells, both of which are closely related to renal fibrosis. Thus, cell cycle dysregulation of renal cells is a potential therapeutic target for the treatment of renal fibrosis. In this review, we focus on cell cycle regulation of renal cells in healthy and diseased kidney, discussing the role of cell cycle dysregulation of renal cells in renal fibrosis. Better understanding of the function of cell cycle dysregulation in renal fibrosis is essential for the development of therapeutics to halt renal fibrosis progression or promote regression.
    Keywords:  cell cycle arrest; cell senescence; over proliferation; renal fibrosis; senescence associated secretory phenotype
    DOI:  https://doi.org/10.3389/fcell.2021.714320
  17. World J Hepatol. 2021 Nov 27. 13(11): 1727-1742
    Cystic fibrosis associated liver disease in children.
    Joseph J Valamparampil, Girish L Gupte.
      Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator gene. CF liver disease develops in 5%-10% of patients with CF and is the third leading cause of death among patients with CF after pulmonary disease or lung transplant complications. We review the pathogenesis, clinical presentations, complications, diagnostic evaluation, effect of medical therapies especially CF transmembrane conductance regulator modulators and liver transplantation in CF associated liver disease.
    Keywords:  Cirrhosis; Cystic fibrosis liver disease; Cystic fibrosis transmembrane conductance regulator modulators; Distal intestinal obstructive syndrome; Liver transplantation; Portal hypertension
    DOI:  https://doi.org/10.4254/wjh.v13.i11.1727
  18. World J Clin Cases. 2021 Nov 26. 9(33): 10249-10256
    Autosomal dominant tubulointerstitial kidney disease with a novel heterozygous missense mutation in the uromodulin gene: A case report.
    Li-Ling Zhang, Jia-Ru Lin, Ting-Ting Zhu, Qi Liu, Dong-Mei Zhang, Lin-Wang Gan, Ying Li, San-Tao Ou.
       BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a progressive chronic disease that is inherited in an autosomal dominant fashion. Symptoms include hyperuricemia, gout, interstitial nephritis, renal cysts, and progressive renal damage that can lead to end-stage renal disease. Mutations in the uromodulin gene (UMOD) characterize the ADTKD-UMOD clinical subtype of this disease. To date, > 100 UMOD mutations have been identified. Early diagnosis of ADTKD-UMOD is important to treat the disease, slow down disease progression, and facilitate the identification of potentially affected family members.
    CASE SUMMARY: We report a 40-year-old man harboring a novel heterozygous missense mutation in UMOD (c.554G>T; p. Arg185Leu). The patient had hyperuricemia, gout, and chronic kidney disease. The same mutation was detected in his daughter, aunt and cousin.
    CONCLUSION: A single nucleotide substitution in exon 3 of UMOD was responsible for the heterozygous missense mutation (c.554G>T, p.Arg185Leu).
    Keywords:  Autosomal dominant tubulointerstitial kidney disease; Case report; Hyperuricemia; Mutation; Uromodulin gene
    DOI:  https://doi.org/10.12998/wjcc.v9.i33.10249
  19. Proc Natl Acad Sci U S A. 2021 Dec 21. pii: e2105192118. [Epub ahead of print]118(51):
    N6-methyladenosine (m6A) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells.
    Kang-Xuan Jin, Rujuan Zuo, Konstantinos Anastassiadis, Arne Klungland, Carsten Marr, Adam Filipczyk.
      N6-methyladenosine (m6A) deposition on messenger RNA (mRNA) controls embryonic stem cell (ESC) fate by regulating the mRNA stabilities of pluripotency and lineage transcription factors (TFs) [P. J. Batista et al., Cell Stem Cell 15, 707-719 (2014); Y. Wang et al., Nat. Cell Biol. 16, 191-198 (2014); and S. Geula et al., Science 347, 1002-1006 (2015)]. If the mRNAs of these two TF groups become stabilized, it remains unclear how the pluripotency or lineage commitment decision is implemented. We performed noninvasive quantification of Nanog and Oct4 TF protein levels in reporter ESCs to define cell-state dynamics at single-cell resolution. Long-term single-cell tracking shows that immediate m6A depletion by Mettl3 knock-down in serum/leukemia inhibitory factor supports both pluripotency maintenance and its departure. This is mediated by differential and opposing signaling pathways. Increased FGF5 mRNA stability activates pErk, leading to Nanog down-regulation. FGF5-mediated coactivation of pAkt reenforces Nanog expression. In formative stem cells poised toward differentiation, m6A depletion activates both pErk and pAkt, increasing the propensity for mesendodermal lineage induction. Stable m6A depletion by Mettl3 knock-out also promotes pErk activation. Higher pErk counteracts the pluripotency exit delay exhibited by stably m6A-depleted cells upon differentiation. At single-cell resolution, we illustrate that decreasing m6A abundances activates pErk and pAkt-signaling, regulating pluripotency departure.
    Keywords:  formative stem cells; m6A; pluripotency; signaling; single-cell resolution
    DOI:  https://doi.org/10.1073/pnas.2105192118
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