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Edward E. Morrisey

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https://www.readbyqxmd.com/read/29657097/single-cell-transcriptomic-profiling-of-pluripotent-stem-cell-derived-scgb3a2-airway-epithelium
#1
Katherine B McCauley, Konstantinos-Dionysios Alysandratos, Anjali Jacob, Finn Hawkins, Ignacio S Caballero, Marall Vedaie, Wenli Yang, Katherine J Slovik, Michael Morley, Gianni Carraro, Seunghyi Kook, Susan H Guttentag, Barry R Stripp, Edward E Morrisey, Darrell N Kotton
Lung epithelial lineages have been difficult to maintain in pure form in vitro, and lineage-specific reporters have proven invaluable for monitoring their emergence from cultured pluripotent stem cells (PSCs). However, reporter constructs for tracking proximal airway lineages generated from PSCs have not been previously available, limiting the characterization of these cells. Here, we engineer mouse and human PSC lines carrying airway secretory lineage reporters that facilitate the tracking, purification, and profiling of this lung subtype...
April 9, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29587138/basal-cells-in-lung-development-and-repair
#2
Edward E Morrisey
Basal cells are an important stem cell lineage in many tissues, including the lung. In this issue of Developmental Cell, Yang et. al. (2018) find that basal cells emerge very early in lung development and that a subset of these contributes to the expansive epithelial wound response observed after influenza injury.
March 26, 2018: Developmental Cell
https://www.readbyqxmd.com/read/29489752/regeneration-of-the-lung-alveolus-by-an-evolutionarily-conserved-epithelial-progenitor
#3
William J Zacharias, David B Frank, Jarod A Zepp, Michael P Morley, Farrah A Alkhaleel, Jun Kong, Su Zhou, Edward Cantu, Edward E Morrisey
Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung...
February 28, 2018: Nature
https://www.readbyqxmd.com/read/29328793/novel-molecular-and-phenotypic-insights-into-congenital-lung-malformations
#4
Daniel T Swarr, William H Peranteau, Jennifer Pogoriler, David B Frank, N Scott Adzick, Holly L Hedrick, Mike Morley, Su Zhou, Edward E Morrisey
RATIONALE: Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects as they are often surgically resected. OBJECTIVES: To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. METHODS: Clinical data, and lung tissue for DNA, RNA, and histology were obtained from 58 infants undergoing surgical resection of a congenital lung lesion...
January 12, 2018: American Journal of Respiratory and Critical Care Medicine
https://www.readbyqxmd.com/read/29133519/deep-rna-sequencing-uncovers-a-repertoire-of-human-macrophage-long-intergenic-noncoding-rnas-modulated-by-macrophage-activation-and-associated-with-cardiometabolic-diseases
#5
Hanrui Zhang, Chenyi Xue, Ying Wang, Jianting Shi, Xuan Zhang, Wenjun Li, Sara Nunez, Andrea S Foulkes, Jennie Lin, Christine C Hinkle, Wenli Yang, Edward E Morrisey, Daniel J Rader, Mingyao Li, Muredach P Reilly
BACKGROUND: Sustained and dysfunctional macrophage activation promotes inflammatory cardiometabolic disorders, but the role of long intergenic noncoding RNA (lincRNA) in human macrophage activation and cardiometabolic disorders is poorly defined. Through transcriptomics, bioinformatics, and selective functional studies, we sought to elucidate the lincRNA landscape of human macrophages. METHODS AND RESULTS: We used deep RNA sequencing to assemble the lincRNA transcriptome of human monocyte-derived macrophages at rest and following stimulation with lipopolysaccharide and IFN-γ (interferon γ) for M1 activation and IL-4 (interleukin 4) for M2 activation...
November 13, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29056552/hemodynamic-forces-sculpt-developing-heart-valves-through-a-klf2-wnt9b-paracrine-signaling-axis
#6
Lauren M Goddard, Anne-Laure Duchemin, Harini Ramalingan, Bingruo Wu, Mei Chen, Sharika Bamezai, Jisheng Yang, Li Li, Michael P Morley, Tao Wang, Marielle Scherrer-Crosbie, David B Frank, Kurt A Engleka, Stephen C Jameson, Edward E Morrisey, Thomas J Carroll, Bin Zhou, Julien Vermot, Mark L Kahn
Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here, we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b...
November 6, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29033129/genome-nuclear-lamina-interactions-regulate-cardiac-stem-cell-lineage-restriction
#7
Andrey Poleshko, Parisha P Shah, Mudit Gupta, Apoorva Babu, Michael P Morley, Lauren J Manderfield, Jamie L Ifkovits, Damelys Calderon, Haig Aghajanian, Javier E Sierra-Pagán, Zheng Sun, Qiaohong Wang, Li Li, Nicole C Dubois, Edward E Morrisey, Mitchell A Lazar, Cheryl L Smith, Jonathan A Epstein, Rajan Jain
Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina...
October 19, 2017: Cell
https://www.readbyqxmd.com/read/28965766/differentiation-of-human-pluripotent-stem-cells-into-functional-lung-alveolar-epithelial-cells
#8
Anjali Jacob, Michael Morley, Finn Hawkins, Katherine B McCauley, J C Jean, Hillary Heins, Cheng-Lun Na, Timothy E Weaver, Marall Vedaie, Killian Hurley, Anne Hinds, Scott J Russo, Seunghyi Kook, William Zacharias, Matthias Ochs, Katrina Traber, Lee J Quinton, Ana Crane, Brian R Davis, Frances V White, Jennifer Wambach, Jeffrey A Whitsett, F Sessions Cole, Edward E Morrisey, Susan H Guttentag, Michael F Beers, Darrell N Kotton
Lung alveoli, which are unique to air-breathing organisms, have been challenging to generate from pluripotent stem cells (PSCs) in part because there are limited model systems available to provide the necessary developmental roadmaps for in vitro differentiation. Here we report the generation of alveolar epithelial type 2 cells (AEC2s), the facultative progenitors of lung alveoli, from human PSCs. Using multicolored fluorescent reporter lines, we track and purify human SFTPC+ alveolar progenitors as they emerge from endodermal precursors in response to stimulation of Wnt and FGF signaling...
October 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28886382/distinct-mesenchymal-lineages-and-niches-promote-epithelial-self-renewal-and-myofibrogenesis-in-the-lung
#9
Jarod A Zepp, William J Zacharias, David B Frank, Christina A Cavanaugh, Su Zhou, Michael P Morley, Edward E Morrisey
The lung is an architecturally complex organ comprising a heterogeneous mixture of various epithelial and mesenchymal lineages. We use single-cell RNA sequencing and signaling lineage reporters to generate a spatial and transcriptional map of the lung mesenchyme. We find that each mesenchymal lineage has a distinct spatial address and transcriptional profile leading to unique niche regulatory functions. The mesenchymal alveolar niche cell is Wnt responsive, expresses Pdgfrα, and is critical for alveolar epithelial cell growth and self-renewal...
September 7, 2017: Cell
https://www.readbyqxmd.com/read/28589954/wnt10a-mutation-causes-ectodermal-dysplasia-by-impairing-progenitor-cell-proliferation-and-klf4-mediated-differentiation
#10
Mingang Xu, Jeremy Horrell, Melinda Snitow, Jiawei Cui, Heather Gochnauer, Camille M Syrett, Staci Kallish, John T Seykora, Fei Liu, Dany Gaillard, Jonathan P Katz, Klaus H Kaestner, Brooke Levin, Corinne Mansfield, Jennifer E Douglas, Beverly J Cowart, Michael Tordoff, Fang Liu, Xuming Zhu, Linda A Barlow, Adam I Rubin, John A McGrath, Edward E Morrisey, Emily Y Chu, Sarah E Millar
Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4...
June 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28546511/the-nanci-nkx2-1-gene-duplex-buffers-nkx2-1-expression-to-maintain-lung-development-and-homeostasis
#11
Michael J Herriges, David J Tischfield, Zheng Cui, Michael P Morley, Yumiao Han, Apoorva Babu, Su Li, MinMin Lu, Isis Cendan, Benjamin A Garcia, Stewart A Anderson, Edward E Morrisey
A subset of long noncoding RNAs (lncRNAs) is spatially correlated with transcription factors (TFs) across the genome, but how these lncRNA-TF gene duplexes regulate tissue development and homeostasis is unclear. We identified a feedback loop within the NANCI (Nkx2.1-associated noncoding intergenic RNA)-Nkx2.1 gene duplex that is essential for buffering Nkx2.1 expression, lung epithelial cell identity, and tissue homeostasis. Within this locus, Nkx2.1 directly inhibits NANCI, while NANCI acts in cis to promote Nkx2...
May 1, 2017: Genes & Development
https://www.readbyqxmd.com/read/28514664/lack-of-mttp-activity-in-pluripotent-stem-cell-derived-hepatocytes-and-cardiomyocytes-abolishes-apob-secretion-and-increases-cell-stress
#12
Ying Liu, Donna M Conlon, Xin Bi, Katherine J Slovik, Jianting Shi, Hailey I Edelstein, John S Millar, Ali Javaheri, Marina Cuchel, Evanthia E Pashos, Jahangir Iqbal, M Mahmood Hussain, Robert A Hegele, Wenli Yang, Stephen A Duncan, Daniel J Rader, Edward E Morrisey
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTPR46G ), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28388432/large-diverse-population-cohorts-of-hipscs-and-derived-hepatocyte-like-cells-reveal-functional-genetic-variation-at-blood-lipid-associated-loci
#13
Evanthia E Pashos, YoSon Park, Xiao Wang, Avanthi Raghavan, Wenli Yang, Deepti Abbey, Derek T Peters, Juan Arbelaez, Mayda Hernandez, Nicolas Kuperwasser, Wenjun Li, Zhaorui Lian, Ying Liu, Wenjian Lv, Stacey L Lytle-Gabbin, Dawn H Marchadier, Peter Rogov, Jianting Shi, Katherine J Slovik, Ioannis M Stylianou, Li Wang, Ruilan Yan, Xiaolan Zhang, Sekar Kathiresan, Stephen A Duncan, Tarjei S Mikkelsen, Edward E Morrisey, Daniel J Rader, Christopher D Brown, Kiran Musunuru
Genome-wide association studies have struggled to identify functional genes and variants underlying complex phenotypes. We recruited a multi-ethnic cohort of healthy volunteers (n = 91) and used their tissue to generate induced pluripotent stem cells (iPSCs) and hepatocyte-like cells (HLCs) for genome-wide mapping of expression quantitative trait loci (eQTLs) and allele-specific expression (ASE). We identified many eQTL genes (eGenes) not observed in the comparably sized Genotype-Tissue Expression project's human liver cohort (n = 96)...
April 6, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28388428/a-drug-screen-using-human-ipsc-derived-hepatocyte-like-cells-reveals-cardiac-glycosides-as-a-potential-treatment-for-hypercholesterolemia
#14
Max A Cayo, Sunil K Mallanna, Francesca Di Furio, Ran Jing, Lauren B Tolliver, Matthew Bures, Amanda Urick, Fallon K Noto, Evanthia E Pashos, Matthew D Greseth, Maciej Czarnecki, Paula Traktman, Wenli Yang, Edward E Morrisey, Markus Grompe, Daniel J Rader, Stephen A Duncan
Efforts to identify pharmaceuticals to treat heritable metabolic liver diseases have been hampered by the lack of models. However, cells with hepatocyte characteristics can be produced from induced pluripotent stem cells (iPSCs). Here, we have used hepatocyte-like cells generated from homozygous familial hypercholesterolemia (hoFH) iPSCs to identify drugs that can potentially be repurposed to lower serum LDL-C. We found that cardiac glycosides reduce the production of apolipoprotein B (apoB) from human hepatocytes in culture and the serum of avatar mice harboring humanized livers...
April 6, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28330813/atp-binding-cassette-transporter-a1-deficiency-in-human-induced-pluripotent-stem-cell-derived-hepatocytes-abrogates-hdl-biogenesis-and-enhances-triglyceride-secretion
#15
Xin Bi, Evanthia E Pashos, Marina Cuchel, Nicholas N Lyssenko, Mayda Hernandez, Antonino Picataggi, James McParland, Wenli Yang, Ying Liu, Ruilan Yan, Christopher Yu, Stephanie L DerOhannessian, Michael C Phillips, Edward E Morrisey, Stephen A Duncan, Daniel J Rader
Despite the recognized role of the ATP-binding Cassette Transporter A1 (ABCA1) in high-density lipoprotein (HDL) metabolism, our understanding of ABCA1 deficiency in human hepatocytes is limited. To define the functional effects of human hepatocyte ABCA1 deficiency, we generated induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from Tangier disease (TD) and matched control subjects. Control HLCs exhibited robust cholesterol efflux to apolipoprotein A-I (apoA-I) and formed nascent HDL particles...
April 2017: EBioMedicine
https://www.readbyqxmd.com/read/27957616/developmental-pathways-in-lung-regeneration
#16
REVIEW
Collin T Stabler, Edward E Morrisey
The key processes of lung development have been elucidated in the past several decades, helping to identify and characterize the resident progenitor cells that ultimately generate the mature organ. The adult lung is a complex organ consisting in scores of different cell lineages that are remarkably quiescent in the absence of injury. Despite low cellular turnover, the lung can respond quickly and dramatically to acute damage, with spatially restricted stem and progenitor cells re-entering the cell cycle and differentiating to promote repair...
March 2017: Cell and Tissue Research
https://www.readbyqxmd.com/read/27880906/emergence-of-a-wave-of-wnt-signaling-that-regulates-lung-alveologenesis-by-controlling-epithelial-self-renewal-and-differentiation
#17
David B Frank, Tien Peng, Jarod A Zepp, Melinda Snitow, Tiffaney L Vincent, Ian J Penkala, Zheng Cui, Michael J Herriges, Michael P Morley, Su Zhou, Min Min Lu, Edward E Morrisey
Alveologenesis is the culmination of lung development and involves the correct temporal and spatial signals to generate the delicate gas exchange interface required for respiration. Using a Wnt-signaling reporter system, we demonstrate the emergence of a Wnt-responsive alveolar epithelial cell sublineage, which arises during alveologenesis, called the axin2+ alveolar type 2 cell, or AT2Axin2 . The number of AT2Axin2 cells increases substantially during late lung development, correlating with a wave of Wnt signaling during alveologenesis...
November 22, 2016: Cell Reports
https://www.readbyqxmd.com/read/27780343/gene-editing-and-genetic-lung-disease-basic-research-meets-therapeutic-application
#18
REVIEW
Deepthi Alapati, Edward E Morrisey
Although our understanding of the genetics and pathology of congenital lung diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin deficiency is extensive, treatment options are lacking. Because the lung is a barrier organ in direct communication with the external environment, targeted delivery of gene corrective technologies to the respiratory system via intratracheal or intranasal routes is an attractive option for therapy. CRISPR/Cas9 gene-editing technology is a promising approach to repairing or inactivating disease-causing mutations...
March 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/27694472/neutrophils-promote-alveolar-epithelial-regeneration-by-enhancing-type-ii-pneumocyte-proliferation-in-a-model-of-acid-induced-acute-lung-injury
#19
Andrew J Paris, Yuhong Liu, Junjie Mei, Ning Dai, Lei Guo, Lynn A Spruce, Kristin M Hudock, Jacob S Brenner, William J Zacharias, Hankun D Mei, April R Slamowitz, Kartik Bhamidipati, Michael F Beers, Steven H Seeholzer, Edward E Morrisey, G Scott Worthen
Alveolar epithelial regeneration is essential for resolution of the acute respiratory distress syndrome (ARDS). Although neutrophils have traditionally been considered mediators of epithelial damage, recent studies suggest they promote type II pneumocyte (AT2) proliferation, which is essential for regenerating alveolar epithelium. These studies did not, however, evaluate this relationship in an in vivo model of alveolar epithelial repair following injury. To determine whether neutrophils influence alveolar epithelial repair in vivo, we developed a unilateral acid injury model that creates a severe yet survivable injury with features similar to ARDS...
December 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27578795/ezh2-restricts-the-smooth-muscle-lineage-during-mouse-lung-mesothelial-development
#20
Melinda Snitow, MinMin Lu, Lan Cheng, Su Zhou, Edward E Morrisey
During development, the lung mesoderm generates a variety of cell lineages, including airway and vascular smooth muscle. Epigenetic changes in adult lung mesodermal lineages are thought to contribute towards diseases such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, although the factors that regulate early lung mesoderm development are unknown. We show in mouse that the PRC2 component Ezh2 is required to restrict smooth muscle differentiation in the developing lung mesothelium...
October 15, 2016: Development
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