KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

Thomas Braun

Prof. Dr. med. Dr. rer. nat. Thomas Braun

Max Planck Institute for Heart and Lung Research
Ludwigstrasse 43; 61231 Bad Nauheim

+49 6032 7051102
Susanne Herold

Prof. Dr. med. Susanne Herold , PhD

Coordinator

Justus Liebig University
Department of Internal Medicine II
Klinikstr. 33; 35392 Giessen

+49-641-985-42552

Novel strategies for therapeutic programming and delivery of mesenchymal stem cells to improve outcome of influenza virus-induced lung injury

Summary

Mesenchymal stem cells (MSC) have promising therapeutic potential in different forms of acute lung injury (ALI), and are now in first clinical trials. However, the molecular mechanisms underlying injury- or pathogen-related beneficial effects within defined niches of the affected lung are mostly unknown. Likewise, the mechanisms by which therapeutically applied MSC of different sources, such as bone marrow or adipose tissue, and lung-resident MSC (rMSC) sense injury during viral lung infections have not been comprehensively examined. This project focuses on the functional heterogeneity of MSC and characterizes the molecular interactions between virus-infected lung cells and different subsets of MSC with dedicated anti-viral and organ repair capacity. 
In the first funding period, we used bulk- and single cell (sc)RNA-Seq analyses combined with advanced lung organoid modelling and in vivo infection models to demonstrate that bone marrow-derived MSC (BM-MSC), white adipose tissue-derived MSCs (WAT-MSC) and rMSC represent heterogeneous populations that differ in single cell transcriptional profiles, exerting distinct roles in anti-viral host defense, tissue protection, and lung tissue regeneration (re-alveolarization). MSC of different origin could be primed in an injury-specific way to effectively support (re)generation of the alveolar compartment, e.g. by IV-specific preconditioning and by TLR3 ligands ex vivo, and in IV- and LPS-injury models in vivo. Regarding the potent antiviral and tissue-protective effects of MSC, we identified a type I IFN-dependent cross-talk as the underlying signalling event between BM-MSC and the IV-infected AEC, both in in vitro models and after intrapulmonary delivery of BM-MSC into IV-infected WT or IFNAR-/- mice in vivo.
In the upcoming funding period, we will (i) molecularly and functionally characterize MSC clusters defined by distinct gene expression profiles, which are highly supportive for (re)alveolarization in lung organoid models and for alveolar repair in in vivo viral infection models. We will determine whether e.g. SPARC, SERPINF1, IGF1 and CSF1/2 identified to be upregulated in injured lung MSC in our RNA-seq analyses account - among others - for the regenerative potential of MSC, or might even substitute for MSC supernatants. To investigate further candidate molecules; we will (ii) define the functional relevance of TLR-responses induced in MSC during IV infection and/or LPS challenge using gain- and loss-of-function approaches in vivo in lung injury models; and (iii) validate our findings in human GCP-produced clinical-grade MSC in human ex vivo models, applying strategies such as disease-specific pre-conditioning, gene transfer, and genome editing to endow human MSC with defined genetic programs and beneficial factors to ultimately use them in first-in-human trials.

Publications

European guidelines on perinatal care: corticosteroids for women at risk of preterm birth

J Matern Fetal Neonatal Med 2023 Dec;36(1):2160628. doi: 10.1080/14767058.2022.2160628



Nicotine promotes e-cigarette vapour-induced lung inflammation and structural alterations

Eur Respir J 2023 Apr 27:2200951. doi: 10.1183/13993003.00951-2022



Autoantibodies are highly prevalent in non-SARS-CoV-2 respiratory infections and critical illness

JCI Insight 2023 Feb 8;8(3):e163150. doi: 10.1172/jci.insight.163150

Notch1 Induces Defective Epithelial Surfactant Processing and Pulmonary Fibrosis

Am J Respir Crit Care Med 2023 Feb 1;207(3):283-299. doi: 10.1164/rccm.202105-1284OC


A Tedious Journey: Cardiomyocyte Proliferation Requires More Than S-Phase Entry and Loss of Polyploidization

Circulation 2023 Jan 10;147(2):154-157. doi: 10.1161/CIRCULATIONAHA.122.062784

Spurious transcription causing innate immune responses is prevented by 5-hydroxymethylcytosine

Nat Genet 2023 Jan;55(1):100-111. doi: 10.1038/s41588-022-01252-3








ADAR1 Prevents Autoinflammatory Processes in the Heart Mediated by IRF7

Circ Res 2022 Sep 16;131(7):580-597. doi: 10.1161/CIRCRESAHA.122.320839




Long-COVID – eine neue Herausforderung [Long COVID-a new challenge]

Inn Med (Heidelb) 2022 Aug;63(8):811-812. German. doi: 10.1007/s00108-022-01376-y

Mosaic loss of Y chromosome during aging

Science 2022 Jul 15;377(6603):266-267. doi: 10.1126/science.add0839

Hodgkin Lymphoma after Disseminated Mycobacterium genavense Infection, Germany

Emerg Infect Dis 2022 Jul;28(7):1506-1509. doi: 10.3201/eid2807.220425






A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth

Nat Metab 2022 Jun;4(6):672-682. doi: 10.1038/s42255-022-00584-y




Cyclosporin A Reveals Potent Antiviral Effects in Preclinical Models of SARS-CoV-2 Infection

Am J Respir Crit Care 2022 Apr 15;205(8):964-968. doi: 10.1164/rccm.202108-1830LE


Synthetic developmental biology: Engineering approaches to guide multicellular organization

Stem Cell Reports 2022 Apr 12;17(4):715-733. doi: 10.1016/j.stemcr.2022.02.004

Osteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo

Nat Commun 2022 Feb 24;13(1):1066. doi: 10.1038/s41467-022-28673-2



Locus-Conserved Circular RNA cZNF292 Controls Endothelial Cell Flow Responses

Circ Res 2022 Jan 7;130(1):67-79. doi: 10.1161/CIRCRESAHA.121.320029


Fibroblast growth factor 6 regulates sizing of the muscle stem cell pool

Stem Cell Reports 2021 Dec 14;16(12):2913-2927. doi: 10.1016/j.stemcr.2021.10.006


SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis

Cell 2021 Dec 22; 184(26): 6243–6261.e27, doi: 10.1016/j.cell.2021.11.033


Flower lose, a cell fitness marker, predicts COVID-19 prognosis

EMBO Mol Med 2021 Nov 8;13(11):e13714. doi: 10.15252/emmm.202013714






Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice

Science 2021 Sep 24;373(6562):1537-1540. doi: 10.1126/science.abg5159

CHD4 ensures stem cell lineage fidelity during skeletal muscle regeneration

Stem Cell Reports 2021 Sep 14;16(9):2089-2098. doi: 10.1016/j.stemcr.2021.07.022





Understanding the Host in the Management of Pneumonia. An Official American Thoracic Society Workshop Report

Ann Am Thorac Soc 2021 Jul;18(7):1087-1097. doi: 10.1513/AnnalsATS.202102-209ST

Directed Evolution of an Enhanced POU Reprogramming Factor for Cell Fate Engineering

Mol Biol Evol 2021 Jun 25;38(7):2854-2868. doi: 10.1093/molbev/msab075

Protocol for the generation of murine bronchiolospheres

STAR Protoc 2021 Jun 11;2(2):100594. doi: 10.1016/j.xpro.2021.100594


An Insight into Giant Cell Arteritis Pathogenesis: Evidence for Oxidative Stress and SIRT1 Downregulation

Antioxidants (Basel) 2021 May 31;10(6):885. doi: 10.3390/antiox10060885


WASP: a versatile, web-accessible single cell RNA-Seq processing platform

BMC Genomics 2021 Mar 18;22(1):195. doi: 10.1186/s12864-021-07469-6


Phosphoproteomics of the developing heart identifies PERM1 - An outer mitochondrial membrane protein

J Mol Cell Cardiol 2021 May;154:41-59. doi: 10.1016/j.yjmcc.2021.01.010



CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension

Eur Respir J 2021 Apr 1;57(4):1901192. doi: 10.1183/13993003.01192-2019

Control of endothelial quiescence by FOXO-regulated metabolites

Nat Cell Biol 2021 Apr;23(4):413-423. doi: 10.1038/s41556-021-00637-6

Immunoglobulin deficiency as an indicator of disease severity in patients with COVID-19

Am J Physiol Lung Cell Mol Physiol 2021 Apr 1;320(4):L590-L599. doi: 10.1152/ajplung.00359.2020

The complex role of SIRT7 in p53 stabilization: nucleophosmin joins the debate

Mol Cell Oncol 2021 Mar 31;8(3):1896349. doi: 10.1080/23723556.2021.1896349


WASP: a versatile, web-accessible single cell RNA-Seq processing platform

BMC Genomics 2021 Mar 18;22(1):195. doi: 10.1186/s12864-021-07469-6


Cardiomyocytes-specific deletion of monoamine oxidase B reduces irreversible myocardial ischemia/reperfusion injury

Free Radic Biol Med 2021 Mar;165:14-23. doi: 10.1016/j.freeradbiomed.2021.01.020


The long and winding road of cardiomyocyte maturation

Cardiovasc Res 2021 Feb 22;117(3):712-726. doi: 10.1093/cvr/cvaa159


SIRT7-dependent deacetylation of NPM promotes p53 stabilization following UV-induced genotoxic stress

Proc Natl Acad Sci U S A 2021 Feb 2;118(5):e2015339118. doi: 10.1073/pnas.2015339118

Imaging lung regeneration by light sheet microscopy

Histochem Cell Biol 2021 Feb;155(2):271-277. doi: 10.1007/s00418-020-01903-8

Chicken Interspecies Chimerism Unveils Human Pluripotency

Stem Cell Reports 2021 Jan 12;16(1):39-55. doi: 10.1016/j.stemcr.2020.11.014

Targeting histone acetylation in pulmonary hypertension and right ventricular hypertrophy

Br J Pharmacol 2021 Jan;178(1):54-71. doi: 10.1111/bph.14932


Identification of a Repair-Supportive Mesenchymal Cell Population during Airway Epithelial Regeneration

Cell Rep 2020 Dec 22;33(12):108549. doi: 10.1016/j.celrep.2020.108549

GnRH neurogenesis depends on embryonic pheromone receptor expression

Mol Cell Endocrinol 2020 Dec 1;518:111030. doi: 10.1016/j.mce.2020.111030

Profiling the Murine SUMO Proteome in Response to Cardiac Ischemia and Reperfusion Injury

Molecules 2020 Nov 27;25(23):5571. doi: 10.3390/molecules25235571



Linc-MYH configures INO80 to regulate muscle stem cell numbers and skeletal muscle hypertrophy

EMBO J 2020 Nov 16;39(22):e105098. doi: 10.15252/embj.2020105098

Impact of litter size on survival, growth and lung alveolarization of newborn mouse pups

Ann Anat 2020 Nov;232:151579. doi: 10.1016/j.aanat.2020.151579



multicrispr: gRNA design for prime editing and parallel targeting of thousands of targets

Life Sci Alliance 2020 Sep 9;3(11):e202000757. doi: 10.26508/lsa.202000757


Besnoitia besnoiti-driven endothelial host cell cycle alteration

Parasitol Res 2020 Aug;119(8):2563-2577. doi: 10.1007/s00436-020-06744-x

The A-to-I RNA Editing Enzyme Adar1 Is Essential for Normal Embryonic Cardiac Growth and Development

Circ Res 2020 Jul 31;127(4):550-552. doi: 10.1161/CIRCRESAHA.120.316932

SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1

Sci Adv 2020 Jul 24;6(30):eaaz2590. doi: 10.1126/sciadv.aaz2590

RUNX1: an emerging therapeutic target for cardiovascular disease

Cardiovasc Res 2020 Jul 1;116(8):1410-1423. doi: 10.1093/cvr/cvaa034

Suppression of p38-MAPK endows endoderm propensity to human embryonic stem cells

Biochem Biophys Res Commun 2020 Jun 30;527(3):811-817. doi: 10.1016/j.bbrc.2020.04.119

Update on the "Choosing Wisely" initiative in infectious diseases in Germany

Infection 2020 Jun;48(3):317-321. doi: 10.1007/s15010-020-01400-z




Signal regulators of human naïve pluripotency

Exp Cell Res 2020 Apr 15;389(2):111924. doi: 10.1016/j.yexcr.2020.111924



Pro-opiomelanocortin Neurons and the Transcriptional Regulation of Motivated Exercise

Exerc Sport Sci Rev 2020 Apr;48(2):74-82. doi: 10.1249/JES.0000000000000219


Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

J Cell Mol Med 2020 Mar;24(6):3534-3548. doi: 10.1111/jcmm.15043

Toward a universal flu vaccine

Science 2020 376(6480): 852-53 doi: 10.1126/science.aba2754

Keeping Fibrotic Responses in Contractile Tissues at Bay: The Plot t(Hic1)ens

Cell Stem Cell 2020 Feb 6;26(2):129-130. doi: 10.1016/j.stem.2019.12.010



The CalcR-PKA-Yap1 Axis Is Critical for Maintaining Quiescence in Muscle Stem Cells

Cell Rep 2019 Nov 19;29(8):2154-2163.e5. doi: 10.1016/j.celrep.2019.10.057

Gpr126 (Adgrg6) is expressed in cell types known to be exposed to mechanical stimuli

Ann N Y Acad Sci 2019 Nov;1456(1):96-108. doi: 10.1111/nyas.14135

Exploration of Physiological and Pathophysiological Implications of miRNA-143 and miRNA-145 in Cerebral Arteries

J Cardiovasc Pharmacol 2019 Nov;74(5):409-419. doi: 10.1097/FJC.0000000000000735

IRE1 Signaling As a Putative Therapeutic Target in Influenza Virus-induced Pneumonia

Am J Respir Cell Mol Biol 2019 Oct;61(4):537-540. doi: 10.1165/rcmb.2019-0123LE


Influenza A Virus Infection Induces Apical Redistribution of Na+, K+-ATPase in Lung Epithelial Cells In Vitro and In Vivo

Am J Respir Cell Mol Biol 2019, Sep;61(3):395-398. doi: 10.1165/rcmb.2019-0096LE.

Update in Lung Infections and Tuberculosis 2018

Am J Respir Crit Care Med 2019 Aug 15;200(4):414-422. doi: 10.1164/rccm.201903-0606UP






Bronchioalveolar stem cells are a main source for regeneration of distal lung epithelia in vivo

EMBO J 2019 Jun 17;38(12):e102099. doi: 10.15252/embj.2019102099

Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET

J Exp Med 2019 Jun 3;216(6):1377-1395. doi: 10.1084/jem.20181394

Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate

Cell Res 2019 Jun;29(6):486-501. doi: 10.1038/s41422-019-0168-1

Illumination of cell cycle progression by multi-fluorescent sensing system

Cell Cycle 2019 Jun;18(12):1364-1378. doi: 10.1080/15384101.2019.1618117


Alternative Oxidase Attenuates Cigarette Smoke-induced Lung Dysfunction and Tissue Damage

Am J Respir Cell Mol Biol 2019 May;60(5):515-522. doi: 10.1165/rcmb.2018-0261OC


CDK1-mediated phosphorylation at H2B serine 6 is required for mitotic chromosome segregation

J Cell Biol 2019 Apr 1;218(4):1164-1181. doi: 10.1083/jcb.201806057



Hematopoietic Deficiency of the Long Noncoding RNA MALAT1 Promotes Atherosclerosis and Plaque Inflammation

Circulation 2019 Mar 5;139(10):1320-1334. doi: 10.1161/CIRCULATIONAHA.117.029015

Transition of inner cell mass to embryonic stem cells: mechanisms, facts, and hypotheses

Cell Mol Life Sci 2019 Mar;76(5):873-892. doi: 10.1007/s00018-018-2965-y

Connect-four: genomic analyses of regenerating stem cells identifies zygotic Dux factors as tumor initiators

Mol Cell Oncol 2019 Feb 8;6(2):1565469. doi: 10.1080/23723556.2019.1565469


Human cardiomyocytes undergo enhanced maturation in embryonic stem cell-derived organoid transplants

Biomaterials 2019 Feb;192:537-550. doi: 10.1016/j.biomaterials.2018.11.033



The AB loop of oncostatin M (OSM) determines species-specific signaling in humans and mice

J Biol Chem 2018 Dec 28;293(52):20181-20199. doi: 10.1074/jbc.RA118.004375




Single Muscle Fiber Proteomics Reveals Distinct Protein Changes in Slow and Fast Fibers during Muscle Atrophy

J Proteome Res 2018 Oct 5;17(10):3333-3347. doi: 10.1021/acs.jproteome.8b00093




The complex biology of KIT+ cells in the heart

Nat Rev Cardiol 2018 Aug;15(8):443-444. doi: 10.1038/s41569-018-0037-5

MiCEE is a ncRNA-protein complex that mediates epigenetic silencing and nucleolar organization

Nat Genet 2018 Jul;50(7):990-1001. doi: 10.1038/s41588-018-0139-3



A systems immunology approach identifies the collective impact of 5 miRs in Th2 inflammation

JCI Insight 2018 Jun 7;3(11):e97503. doi: 10.1172/jci.insight.97503


Sirtuins in the Cardiovascular System: Potential Targets in Pediatric Cardiology

Pediatr Cardiol 2018 Jun;39(5):983-992. doi: 10.1007/s00246-018-1848-1

Treatment Options for Carbapenem- Resistant Gram-Negative Infections

Dtsch Arztebl Int 2018 May 21;115(20-21):345-352. doi: 10.3238/arztebl.2018.0345










Clonal Expansion of Endothelial Cells Contributes to Ischemia-Induced Neovascularization

Circ Res 2018 Mar 2;122(5):670-677. doi: 10.1161/CIRCRESAHA.117.312310






Runx1 Deficiency Protects Against Adverse Cardiac Remodeling After Myocardial Infarction

Circulation 2018 Jan 2;137(1):57-70. doi: 10.1161/CIRCULATIONAHA.117.028911

Small RNA Sequencing Reveals Dlk1-Dio3 Locus-Embedded MicroRNAs as Major Drivers of Ground-State Pluripotency

Stem Cell Reports 2017 Dec 12;9(6):2081-2096. doi: 10.1016/j.stemcr.2017.10.009





Restoration of Megalin-Mediated Clearance of Alveolar Protein as a Novel Therapeutic Approach for Acute Lung Injury

Am J Respir Cell Mol Biol 2017 Nov;57(5):589-602. doi: 10.1165/rcmb.2016-0358OC


Sirt7 stabilizes rDNA heterochromatin through recruitment of DNMT1 and Sirt1

Biochem Biophys Res Commun 2017 Oct 21;492(3):434-440. doi: 10.1016/j.bbrc.2017.08.081

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

Proc Natl Acad Sci U S A 2017 Oct 3;114(40):E8352-E8361. doi: 10.1073/pnas.1706945114


Cardiomyocyte Regeneration: A Consensus Statement

Circulation 2017 Aug 15;136(7):680-686. doi: 10.1161/CIRCULATIONAHA.117.029343

Perturbations to lysyl oxidase expression broadly influence the transcriptome of lung fibroblasts

Physiol Genomics 2017 Aug 1;49(8):416-429. doi: 10.1152/physiolgenomics.00026.2017

BMP signaling regulates satellite cell-dependent postnatal muscle growth

Development 2017 Aug 1;144(15):2737-2747. doi: 10.1242/dev.144089

Multimodal Regulation of Cardiac Myocyte Proliferation

Circ Res 2017 Jul 21;121(3):293-309. doi: 10.1161/CIRCRESAHA.117.308428

Exosomal tetraspanins mediate cancer metastasis by altering host microenvironment

Oncotarget 2017 Jul 10;8(37):62803-62815. doi: 10.18632/oncotarget.19119

Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy

Dis Model Mech 2017 Jul 1;10(7):881-896. doi: 10.1242/dmm.028910

A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses

EMBO J 2017 Jun 14;36(12):1770-1787. doi: 10.15252/embj.201695748


Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

J Clin Invest 2017 Jun 1;127(6):2235-2248. doi: 10.1172/JCI88725

UROPA: a tool for Universal RObust Peak Annotation

Sci Rep 2017 Jun 1;7(1):2593. doi: 10.1038/s41598-017-02464-y

The "Choosing Wisely" initiative in infectious diseases

Infection 2017 Jun;45(3):263-268. doi: 10.1007/s15010-017-0997-0












Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

Cell Stem Cell 2017 Feb 2;20(2):261-273.e3. doi: 10.1016/j.stem.2016.10.004. Epub 2016 Nov 17. Erratum in: Cell Stem Cell. 2017 Apr 6;20(4):571


Tamoxifen dosing for Cre-mediated recombination in experimental bronchopulmonary dysplasia

Transgenic Res 2017 Feb;26(1):165-170. doi: 10.1007/s11248-016-9987-8

Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology

Dis Model Mech 2017 Feb 1;10(2):163-171. doi: 10.1242/dmm.027839


Sirt7 inhibits Sirt1-mediated activation of Suv39h1

Cell Cycle 2018;17(12):1403-1412. doi: 10.1080/15384101.2018.1486166

Systematic Identification of Genes Regulating Muscle Stem Cell Self-Renewal and Differentiation

Methods Mol Biol 2017;1556:343-353. doi: 10.1007/978-1-4939-6771-1_19

Principal Investigators

Thomas Braun

Prof. Dr. med. Dr. rer. nat. Thomas Braun

Max Planck Institute for Heart and Lung Research
Ludwigstrasse 43; 61231 Bad Nauheim

+49 6032 7051102
Susanne Herold

Prof. Dr. med. Susanne Herold , PhD

Coordinator

Justus Liebig University
Department of Internal Medicine II
Klinikstr. 33; 35392 Giessen

+49-641-985-42552

Project group

  • Margarida Barroso

    Margarida Barroso

    +49-641-985-42713
  • Holger Lörchner

    Dr. Holger Lörchner

    Postdoc

  • Stefan Günther

    Dr. Stefan Günther

    Postdoc

  • Jens Preussner

    Jens Preussner

    PhD student

  • Kerstin Richter

    Kerstin Richter

    Technician