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Schiller Lab

Cell Circuits in Systems Medicine of Lung Disease

The main aim of our research is to understand how cells are wired together into circuits and thereby influence each other in lung health and disease. We study patient and mouse tissues, and organotypic ex vivo models at single cell resolution.

The main aim of our research is to understand how cells are wired together into circuits and thereby influence each other in lung health and disease. We study patient and mouse tissues, and organotypic ex vivo models at single cell resolution.

About our Research

Genes interact in functional gene programs that ultimately constitute health or disease. Gene programs act on the level of individual cells but importantly also at tissue level across multiple cell types. Functionally connected multicellular circuits react as a coordinated unit in immunological responses to environmental challenges and infections. The main aim of this research is to understand how cells are wired together into circuits and thereby influence each other in lung health and disease. We study patient and mouse tissues, and organotypic ex vivo models at single cell resolution. This enables us to reconstruct regulatory cellular circuits and identify fundamental cellular and molecular mechanism of lung disease and regeneration, as well as associated clinically relevant biomarkers.

Single cell genomics is revolutionizing biology and medicine, combining the advantages of bulk sequencing techniques and microscopic analyses of single cells. Rapid technological advances now allow the profiling of genomes, transcriptomes and epigenomes at an unprecedented level of resolution (see https://www.singlecell.de/). We employ the recently developed Drop-seq method, which uses microfluidics to capture single cells along with sets of uniquely barcoded primer beads into nanoliter-sized aqueous droplets. The smart barcoding approach in Drop-seq allows the massively parallel, and thus cost-effective, analysis of mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts’ cell of origin (Macosko et al 2015).

As collaborative member of the Human Cell Atlas (HCA) Initiative we use single cell RNA-seq to unravel the cellular composition of both mouse and human lungs. 

The Lung Cell Atlas will reveal the true complexity of cellular composition and spatial organization of the various multicellular units that constitute human lungs. Together with our HCA and DZL (German Center for Lung Research) partners we are currently starting to develop methodologies and an infrastructure for standardized and validated characterization and integration of single-cell transcriptomic and proteomic data into the spatial context of lung tissue architecture. Already the first draft of the Lung Cell Atlas will include well defined cohorts of chronic lung disease samples (including COPD and IPF) in order to proof feasibility and power of delineating the healthy condition from a continuum of possible disease states in individual humans. A Human Lung Cell Atlas will tremendously accelerate both basic and translational research on lung development and disease.

 

Despite the tremendous interest in ECM biology in the context of regenerative medicine and cancer research, the systematic characterization of extracellular matrix niches is a much underexplored area of research. Lung regeneration depends on the reactivation of developmental programs, where the crosstalk between mesenchyme and epithelium via secreted proteins is essential. In a process called fibrogenesis, several mesenchymal cell populations secrete and assemble a specialized provisional ECM, which acts as a scaffold and master regulator of developmental programs in concert with extracellular morphogens, such as growth factors, cytokines, or chemokines. We recently characterized the murine lung proteome, including its extracellular matrix content and organization, to unprecedented depth, which enabled a protein-centric systems biology view on tissue injury, fibrosis and repair.

We plan to use a variety of state of the art methods including immunofluorescence imaging, mass spectrometry driven proteomics and single cell expression analysis to pinpoint spatio-temporal changes of ECM composition in lung development, injury repair and metastatic colonization. The functional implications of selected proteins are assessed using transgenic mouse lines or CRISPR/Cas9 constructs.

Metazoans evolved ~300 large multidomain extracellular matrix (ECM) proteins, which interact with each other and cells to form elaborate composite biomaterials that shape both the form and function of tissues. To determine the topology of this highly complex and insoluble network at molecular resolution in its tissue context has not been possible due to technical challenges. The recent successful combination of chemical crosslinking with mass spectrometry (CXMS), promises to revolutionize structural biology and protein interaction studies, and opens the way for ECM interactomics in situ. In collaboration with Dr. Richard Scheltema (Utrecht University) we are currently developing several mass spectrometry (MS) methods and software (including CXMS) for structural proteomics of the ECM. Using collision induced dissociation (CID) of labile chemical crosslinkers we recently developed a novel CXMS analysis workflow, utilizing the Q-exactive quadrupole-orbitrap type mass spectrometer. As a proof of concept, we successfully used our new method in combination with protein crystallography and cryo‐EM to obtain the first complete pseudoatomic model of a type‐III CRISPR complex (Benda et al, 2014).

We currently work on ECM protein complex retrieval methods from tissues as well as CXMS approaches to develop and apply `discovery mode´ analysis tools for protein interactions from complex tissue environments.

Genes interact in functional gene programs that ultimately constitute health or disease. Gene programs act on the level of individual cells but importantly also at tissue level across multiple cell types. Functionally connected multicellular circuits react as a coordinated unit in immunological responses to environmental challenges and infections. The main aim of this research is to understand how cells are wired together into circuits and thereby influence each other in lung health and disease. We study patient and mouse tissues, and organotypic ex vivo models at single cell resolution. This enables us to reconstruct regulatory cellular circuits and identify fundamental cellular and molecular mechanism of lung disease and regeneration, as well as associated clinically relevant biomarkers.

Single cell genomics is revolutionizing biology and medicine, combining the advantages of bulk sequencing techniques and microscopic analyses of single cells. Rapid technological advances now allow the profiling of genomes, transcriptomes and epigenomes at an unprecedented level of resolution (see https://www.singlecell.de/). We employ the recently developed Drop-seq method, which uses microfluidics to capture single cells along with sets of uniquely barcoded primer beads into nanoliter-sized aqueous droplets. The smart barcoding approach in Drop-seq allows the massively parallel, and thus cost-effective, analysis of mRNA transcripts from thousands of individual cells simultaneously while remembering transcripts’ cell of origin (Macosko et al 2015).

As collaborative member of the Human Cell Atlas (HCA) Initiative we use single cell RNA-seq to unravel the cellular composition of both mouse and human lungs. 

The Lung Cell Atlas will reveal the true complexity of cellular composition and spatial organization of the various multicellular units that constitute human lungs. Together with our HCA and DZL (German Center for Lung Research) partners we are currently starting to develop methodologies and an infrastructure for standardized and validated characterization and integration of single-cell transcriptomic and proteomic data into the spatial context of lung tissue architecture. Already the first draft of the Lung Cell Atlas will include well defined cohorts of chronic lung disease samples (including COPD and IPF) in order to proof feasibility and power of delineating the healthy condition from a continuum of possible disease states in individual humans. A Human Lung Cell Atlas will tremendously accelerate both basic and translational research on lung development and disease.

 

Despite the tremendous interest in ECM biology in the context of regenerative medicine and cancer research, the systematic characterization of extracellular matrix niches is a much underexplored area of research. Lung regeneration depends on the reactivation of developmental programs, where the crosstalk between mesenchyme and epithelium via secreted proteins is essential. In a process called fibrogenesis, several mesenchymal cell populations secrete and assemble a specialized provisional ECM, which acts as a scaffold and master regulator of developmental programs in concert with extracellular morphogens, such as growth factors, cytokines, or chemokines. We recently characterized the murine lung proteome, including its extracellular matrix content and organization, to unprecedented depth, which enabled a protein-centric systems biology view on tissue injury, fibrosis and repair.

We plan to use a variety of state of the art methods including immunofluorescence imaging, mass spectrometry driven proteomics and single cell expression analysis to pinpoint spatio-temporal changes of ECM composition in lung development, injury repair and metastatic colonization. The functional implications of selected proteins are assessed using transgenic mouse lines or CRISPR/Cas9 constructs.

Metazoans evolved ~300 large multidomain extracellular matrix (ECM) proteins, which interact with each other and cells to form elaborate composite biomaterials that shape both the form and function of tissues. To determine the topology of this highly complex and insoluble network at molecular resolution in its tissue context has not been possible due to technical challenges. The recent successful combination of chemical crosslinking with mass spectrometry (CXMS), promises to revolutionize structural biology and protein interaction studies, and opens the way for ECM interactomics in situ. In collaboration with Dr. Richard Scheltema (Utrecht University) we are currently developing several mass spectrometry (MS) methods and software (including CXMS) for structural proteomics of the ECM. Using collision induced dissociation (CID) of labile chemical crosslinkers we recently developed a novel CXMS analysis workflow, utilizing the Q-exactive quadrupole-orbitrap type mass spectrometer. As a proof of concept, we successfully used our new method in combination with protein crystallography and cryo‐EM to obtain the first complete pseudoatomic model of a type‐III CRISPR complex (Benda et al, 2014).

We currently work on ECM protein complex retrieval methods from tissues as well as CXMS approaches to develop and apply `discovery mode´ analysis tools for protein interactions from complex tissue environments.

Scientists at Schiller Lab

Yuexin Chen

PhD Student

Laurens de Sadeleer

Postdoctoral Fellow

Daniela Haas

Team Assistant Schiller Lab

Ahmed Hassan

MD Student

Lukas Heumos

Doctoral Student (PhD)

Rolf Christoph Jentzsch

MD Student

Prerna Karthaka

PhD Student

Niklas Jonathan Lang

MD Student

Dr. Janine Schniering

Postdoctoral Fellow

Anna Semenova

Doctoral Student (PhD)

Anastasia van den Berg

Lab Manager

Konstantin Wiedemann

MD Student

Dr. Lin Yang

Postdoctoral Fellow

Zhen Zeng

Postdoctoral Fellow

Publications

Contact

Dr. Herbert Schiller

Deputy Director & Team Leader