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Alveolar epithelial regeneration

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
Martin S Taylor, Raghu R Chivukula, Laura C Myers, William R Jeck, Avinash Waghray, Purushothama R Tata, Martin K Selig, Walter J O'Donnell, Carol F Farver, B Taylor Thompson, Jayaraj Rajagopal, Richard L Kradin
Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsies showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages...
February 21, 2018: American Journal of Pathology
Tiankai Xu, Yuyu Zhang, Pengyu Chang, Shouliang Gong, Lihong Shao, Lihua Dong
Since radiotherapy is widely used in managing thoracic tumors, physicians have begun to realize that radiation-induced lung injury (RILI) seriously limits the effects of radiotherapy. Unfortunately, there are still no effective methods for controlling RILI. Over the last few decades numerous studies have reported the beneficial effects of mesenchymal stem cells (MSCs) on tissue repair and regeneration. MSCs can not only differentiate into lung alveolar epithelial cells and secrete anti-inflammatory factors, but they also deliver some vehicles for gene therapy in repairing the injured lung, which provides new ideas for managing RILI...
January 31, 2018: Stem Cell Research & Therapy
Hélène Martin Thomé, David Bourdin, Nicolas Strube, Afchine Saffarzadeh, Jean-Francois Morlock, Guillaume Campard, Charles Evanno, Alain Hoornaert, Pierre Layrolle
For the regeneration of small osseous defects, dental membranes are commonly used in oral and maxillofacial surgery. A new synthetic resorbable membrane has recently demonstrated its biocompatibility and bone regeneration capacity in preclinical studies. This membrane is made of poly-D,L-lactic/glycolic acid 85/15 (PLGA), has a bi-layered structure with a dense film to prevent gingival epithelial cell invasion and a micro-fibrous layer to support osteogenic cells and bone healing. This membrane completely degrades by hydrolysis in 4 to 6 months without signs of inflammation...
January 5, 2018: Journal of Oral Implantology
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
Joo-Hyeon Lee, Tuomas Tammela, Matan Hofree, Jinwook Choi, Nemanja Despot Marjanovic, Seungmin Han, David Canner, Katherine Wu, Margherita Paschini, Dong Ha Bhang, Tyler Jacks, Aviv Regev, Carla F Kim
The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6(+) cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation...
September 7, 2017: Cell
Pedro S Babo, Xinjie Cai, Adelina S Plachokova, Rui L Reis, John Jansen, Manuela E Gomes, X Frank Walboomers
With currently available therapies, full regeneration of lost periodontal tissues after periodontitis cannot be achieved. In this study, a combined compartmentalized system was tested, composed of (1) a platelet lysate (PL)-based construct, which was placed along the root aiming to regenerate the root cementum and periodontal ligament, and (2) a calcium phosphate cement composite incorporated with hyaluronic acid microspheres loaded with PL, aiming to promote the regeneration of alveolar bone. This bi-layered system was assessed in a 3-wall periodontal defect in Wistar rats...
August 17, 2017: Journal of Tissue Engineering and Regenerative Medicine
Rohan R Nadkarni, Soumeya Abed, Jonathan S Draper
The epithelial cells lining the mammalian lung are subjected to constant interaction with the external environment, necessitating robust regeneration strategies to deal with cell loss due to natural turnover or damage arising from inhaled agents or disease. Since lung epithelial function extends beyond respiratory gas exchange to include roles such as immune defense and mucociliary clearance, a diverse complement of epithelial cell types exists that are regionally distributed along the respiratory tree and extensive surface area of the alveolar interface...
August 2, 2017: Chest
Ying Xi, Thomas Kim, Alexis N Brumwell, Ian H Driver, Ying Wei, Victor Tan, Julia R Jackson, Jianming Xu, Dong-Kee Lee, Jeffrey E Gotts, Michael A Matthay, John M Shannon, Harold A Chapman, Andrew E Vaughan
After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5(pos) basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5(pos) basal-like state...
August 2017: Nature Cell Biology
Yusuke Takahashi, Noriyuki Matsutani, Hitoshi Dejima, Takashi Nakayama, Hirofumi Uehara, Masafumi Kawamura
BACKGROUND: Compensatory lung growth (CLG) is a well-established lung regeneration model. However, the sequential mechanisms, including unknown molecular triggers or regulators, remain unclear. Nuclear factor- kappa B (NF-κB) is known to be essential for inflammation and tissue regeneration; therefore, we investigated the role of NF-κB in CLG. METHODS: C57BL/6 J mice underwent either a left pneumonectomy or a thoracotomy (n = 77). Gene microarray analysis was performed to detect genes that were upregulated at 12 h after pneumonectomy...
July 5, 2017: Journal of Biomedical Science
Xiuying Li, Yandong Lai, Jin Li, Mingyi Zou, Chunbin Zou
Oxidative stress impacts normal cellular function leading to the pathogenesis of various diseases including pulmonary illnesses. Protein arginine methyltransferase 4 (PRMT4) is critical for normal lung alveolar epithelial cell development; however, the regulation of PRMT4 within such pulmonary diseases has yet to be elucidated. Using biochemical approaches, we uncovered that peroxide (H2O2) treatment decreases PRMT4 protein stability in murine lung epithelial (MLE12) cells to impede cell migration. Protein kinase glycogen synthase kinase 3β (GSK-3β) interacts with PRMT4 and catalyzes PRMT4 T132 phosphorylation that protects PRMT4 from ubiquitin proteasomal degradation...
September 1, 2017: American Journal of Physiology. Cell Physiology
Yancong Zhang, Yongliang Li, Ruirui Shi, Siqi Zhang, Hao Liu, Yunfei Zheng, Yan Li, Jinglei Cai, Duanqing Pei, Shicheng Wei
BACKGROUND: A number of studies have shown that tooth-like structures can be regenerated using induced pluripotent stem cells and mouse embryonic stem (mES) cells. However, few studies have reported the regeneration of tooth-periodontium complex structures, which are more suitable for clinical tooth transplantation. We established an optimized approach to induce high-odontogenic potential dental epithelium derived from mES cells by temporally controlling bone morphogenic protein 4 (BMP4) function and regenerated tooth-periodontium complex structures in vivo...
June 8, 2017: Stem Cell Research & Therapy
Zeeshan Sheikh, Nader Hamdan, Yuichi Ikeda, Marc Grynpas, Bernhard Ganss, Michael Glogauer
Periodontal disease is categorized by the destruction of periodontal tissues. Over the years, there have been several clinical techniques and material options that been investigated for periodontal defect repair/regeneration. The development of improved biomaterials for periodontal tissue engineering has significantly improved the available treatment options and their clinical results. Bone replacement graft materials, barrier membranes, various growth factors and combination of these have been used. The available bone tissue replacement materials commonly used include autografts, allografts, xenografts and alloplasts...
2017: Biomaterials Research
Juan Shi, Feng Li, Meihui Luo, Jun Wei, Xiaoming Liu
Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema...
2017: Mediators of Inflammation
Andrew J Lechner, Ian H Driver, Jinwoo Lee, Carmen M Conroy, Abigail Nagle, Richard M Locksley, Jason R Rock
To investigate the role of immune cells in lung regeneration, we used a unilateral pneumonectomy model that promotes the formation of new alveoli in the remaining lobes. Immunofluorescence and single-cell RNA sequencing found CD115+ and CCR2+ monocytes and M2-like macrophages accumulating in the lung during the peak of type 2 alveolar epithelial stem cell (AEC2) proliferation. Genetic loss of function in mice and adoptive transfer studies revealed that bone marrow-derived macrophages (BMDMs) traffic to the lung through a CCL2-CCR2 chemokine axis and are required for optimal lung regeneration, along with Il4ra-expressing leukocytes...
July 6, 2017: Cell Stem Cell
John-Poul Ng-Blichfeldt, Joana Alçada, M Angeles Montero, Charlotte H Dean, Uta Griesenbach, Mark J Griffiths, Matthew Hind
BACKGROUND: Molecular pathways that regulate alveolar development and adult repair represent potential therapeutic targets for emphysema. Signalling via retinoic acid (RA), derived from vitamin A, is required for mammalian alveologenesis, and exogenous RA can induce alveolar regeneration in rodents. Little is known about RA signalling in the human lung and its potential role in lung disease. OBJECTIVES: To examine regulation of human alveolar epithelial and endothelial repair by RA, and characterise RA signalling in human emphysema...
June 2017: Thorax
Stephen McGowan
Although pulmonary alveolar interstitial fibroblasts are less specialized than their epithelial and endothelial neighbors, they play essential roles during development and in response to lung injury. At birth, they must adapt to the sudden mechanical changes imposed by the onset of respiration and to a higher ambient oxygen concentration. In diseases such as bronchopulmonary dysplasia and interstitial fibrosis, their adaptive responses are overwhelmed leading to compromised gas-exchange function. Thus, although fibroblasts do not directly participate in gas-exchange, they are essential for creating and maintaining an optimal environment at the alveolar epithelial-endothelial interface...
March 2017: Cell and Tissue Research
Masahito Ebina
Numerous studies have been published investigating the pathologic alterations in various interstitial pneumonias, particularly in idiopathic pulmonary fibrosis (IPF). However, the few existing studies on capillary remodeling, which does not seem to have priority for pathologic diagnosis, are contradictory, with some reporting increased and others reduced vascularization. We hypothesized that these discrepancies were due to the temporal heterogeneity of the lesions in IPF. We subsequently developed original techniques for evaluating vascular density within the alveolar septa and discovered, for the first time, a heterogeneous increase in alveolar capillaries in the lungs of IPF patients...
January 2017: Respiratory Investigation
Lars Knudsen, Clemens Ruppert, Matthias Ochs
Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease...
March 2017: Cell and Tissue Research
Min Yee, William Domm, Robert Gelein, Karen L de Mesy Bentley, R Matthew Kottmann, Patricia J Sime, B Paige Lawrence, Michael A O'Reilly
An aberrant oxygen environment at birth increases the severity of respiratory viral infections later in life through poorly understood mechanisms. Here, we show that alveolar epithelial cell (AEC) 2 cells (AEC2s), progenitors for AEC1 cells, are depleted in adult mice exposed to neonatal hypoxia or hyperoxia. Airway cells expressing surfactant protein (SP)-C and ATP binding cassette subfamily A member 3, alveolar pod cells expressing keratin (KRT) 5, and pulmonary fibrosis were observed when these mice were infected with a sublethal dose of HKx31, H3N2 influenza A virus...
April 2017: American Journal of Respiratory Cell and Molecular Biology
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