The Junior Research Group of Dr. Ivana Mižik “Lung-Microbiota Interactions in Development, Health and Disease” focuses on pre-natal and early post-natal lung development, pulmonary diseases associated with prematurity and the role microbiota play in these processes.
Bronchopulmonary dysplasia (BPD) is among the most common and severe complications of prematurity and the most common chronic lung disease in neonates in developed countries. While the mortality of premature infants was greatly reduced in the last 50 years, BPD remains a major cause of morbidity and mortality in neonatal intensive care unit and one of the leading causes of death in children under the age of five. BPD constitutes a heterogenous disease of multi-factorial origin, which severity is strongly associated with the degree of prematurity, pre-natal and post-natal inflammation, invasive ventilation strategies and exposure to increased levels of oxygen. The lungs of BPD patients are generally characterized by alveolar hypoplasia, dysmorphic pulmonary vasculature, and impaired immune development leading to recurrent respiratory infections in infancy and beyond. Underlying cellular and signaling pathways involved are not well-understood and effective reparative therapies are lacking. In our research we strive to identify the key pathological changes in cellular landscape resulting in the arrest of proper pulmonary development, as well as the role environmental factors, such as microbiota play in these processes.
The work in AG MIZIK pursues the following research topics:
- Understanding the late pre-natal and early post-natal pulmonary cellular landscape. This project focuses on understanding the cellular landscape, as well as dynamic of gene expression and protein composition in the late pre-natal and early post-natal human lung. The results obtained in this study will represent a critical reference point for studies of early post-natal lung diseases and diseases of prematurity, where the underlying pathogenesis remains unknown.
- Understanding the role of diverse epithelial subpopulations in normal post-natal lung development and BPD. Current project focuses on identifying the causal role of selected subpopulations of distal lung epithelial populations during normal postnatal lung development, as well as their specific roles in the development of BPD.
- Role of activated lung macrophages in BPD pathogenesis. This project investigates the behavior of selected macrophage subpopulations and their interactions with other cell populations during normal post-natal lung development, as well as their specific roles in the pathogenesis of BPD.
- Role of microbiota and microbiome in normal post-natal lung development and in the pathogenesis of BPD. Current project focuses on understanding the heterogeneity of lung microbiome in BPD patients and to explore its impact on disease progression, particularly the inflammatory response, inter-cellular communication and immune cell priming.
- Understanding the diverse BPD phenotypes and endotypes. In this comparative study we will aim to identify underlying pathomechanisms in the individual BPD phenotypes and endotypes on cellular and transcriptomic level. This will further allow to select for the most suitable in vitro and in vivo models mimicking the discrete phenotypes, improving the translation from animal models to clinical studies.
- DZL
- DFG (531878612: Die Rolle von Itgam + Lungenmakrophagen bei der Pathogenese und den Langzeitwirkungen der Bronchopulmonalen Dysplasie.)
Ariani Syafitri Rahadian | PhD Student | |||
Sara D’Agostino | PhD Student | |||
Ümran Turan | PhD Student | |||
Renesme L, Lesage F, Cook DP, Achutan A., Zhong S, Hänninen SM, Carpén O, Mižik I*, Thébaud B*.A human single-nuclei atlas reveals novel cell states during the pseudoglandular-to-canalicular transition. Am J Respir Cell Mol BIol, 2025. Doi: 10.1165/rcmb.2024-0244OC
C. Cyr-Depauw, I. Mižik, D.P. Cook, F. Lesage, A Vadivel, L. Renesme, Y. Deng, S. Zhong, Pauline Bardin, L. Xu, M. A. Möbius, J. Marzahn, D. Freund, D. J. Stewart, B. C. Vanderhyden, M. Rüdiger, B. Thébaud. Single-Cell RNA Sequencing to Guide Autologous Preterm Cord Mesenchymal Stromal Cell-Therapy. Am J Respir Crit Care Med, 2025; 211(3):391-406. doi: 10.1164/rccm.202403-0569OC.PMID: 39586004
C. Cyr-Depauw, D.P. Cook, I. Mižik, F. Lesage, A Vadivel, L. Renesme, Y. Deng, S. Zhong, Pauline Bardin, L. Xu, M. A. Möbius, J. Marzahn, D. Freund, D. J. Stewart, B. C. Vanderhyden, M. Rüdiger, B. Thébaud. Single-Cell RNA Sequencing Reveals Repair Features of Human Umbilical Cord Mesenchymal Stromal Cells. Am J Respir Crit Care Med, 2024; 210(6):814-827. doi: 10.1164/rccm.202310-1975OC.PMID: 38564376
Mižíková I, Lesage F, Cyr-Depauw C, Cook DP, Hurskainen M, Hänninen SM, Vadivel A, Bardin P, Zhong S, Carpén O, Vanderhyden B, Thébaud B. Single-cell RNA sequencing-based characterization of resident lung mesenchymal stromal cells in bronchopulmonary dysplasia. Stem Cells
, 2022; 40(5):479-492. doi.org/10.1093/stmcls/sxab023
Mižíková I, Thébaud B. Looking at the developing lung in single-cell resolution. Am J Physiol Lung Cell Mol Physiol
, 2021; 320: L680–L687. doi.org/10.1152/ajplung.00385.2020
Mižíková I.*, Hurskainen M.*, Cook D.P, Andersson N., Cyr-Depauw C., Lesage F., Helle E., Renesme L., Jankov R.P., Heikinheimo M., Vanderhyden B.C., Thébaud B. Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage. Nat Commun,
2021; 12(1):1565. doi.org/10.1038/s41467-021-21865-2
Mižíková I, Pfeffer T, Nardiello C, Surate Solaligue DE, Steenbock H, Tatsukawa H, Silva DM, Vadász I, Herold S, Pease RJ, Iismaa SE, Hitomi K, Seeger W, Brinckman J, Morty RE. Targeting transglutaminase 2 during aberrant alveolarization partially restores extracellular matrix structure but not alveolar architecture in developing lungs. FEBS J
; 2018. 285(16):3056-3076. doi.org/10.1111/febs.14596
Hönig J, Mižíková I,Nardiello C, Surate Solaligue DE, Daume MJ, Vadász I, Mayer K, Herold S, Günter S, Seeger W, Morty RE. Transmission of microRNA antimiRs to Mouse Offspring via the Maternal-Placental-Fetal Unit. RNA
, 2018. 24(6):865-879. doi.org 10.1261/rna.063206.117
Mižíková I, Palumbo F, Tábi T, Herold S, Vadász I, Mayer K, Seeger W, Morty RE. Perturbations to lysyl oxidase expression broadly influence the transcriptome of lung fibroblasts. Physiological Genomics
. 2017. 49(8): p. 416-429. doi.org/10.1152/physiolgenomics.00026.2017
Nardiello C, Mižíková I, Silva DM, Ruiz-Camp J, Mayer K, Vadász I, Herold S, Seeger W, Morty RE. Standardisation of oxygen exposure in the development of mouse models for bronchopulmonary dysplasia. Dis Model Mech
; 2017. 10(2): p. 185-196. doi.org/10.1242/dmm.027086
Mižíková, I and RE Morty. The Extracellular Matrix in Bronchopulmonary Dysplasia: Target and Source. Front Med
(Lausanne), 2015. 2: p. 91. doi.org/10.3389/fmed.2015.00091
Mižíková I, Ruiz-Camp J, Madurga A, Vadász I, Herold S, Mayer K, Seeger W, Morty RE. Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia. Am J Physiol Lung Cell Mol Physiol
, 2015. 308(11): p. L1145- 1158. doi.org/10.1152/ajplung.00039.2015
Nave, AH, Mižíková, I, Niess G, Steenbock H, Reichenberger F, Talavera ML, Veit F, Herold S, Mayer K, Vadász I, Weissmann N, Seeger W, Brinckmann J, Morty RE. Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol
, 2014. 34(7): p. 1446-58. doi.org 10.1161/ATVBAHA.114.30353