Publications

• Seifert, R., Markert, S., Britz, S., Perschin, V., Erbacher, C., Stigloher, C., Kollmannsberger, P.: DeepCLEM: automated registration for correlative light and electron microscopy using deep learning [version 1; peer review: awaiting peer review]. F1000Research. 9, (2020).
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  @article{10.12688/f1000research.27158.1, author = {Seifert, R and Markert, SM and Britz, S and Perschin, V and Erbacher, C and Stigloher, C and Kollmannsberger, P}, journal = {F1000Research}, keywords = {philipkollmannsberger}, number = 1275, title = {DeepCLEM: automated registration for correlative light and electron microscopy using deep learning [version 1; peer review: awaiting peer review]}, volume = 9, year = 2020 }

  %0 Journal Article %1 10.12688/f1000research.27158.1 %A Seifert, R %A Markert, SM %A Britz, S %A Perschin, V %A Erbacher, C %A Stigloher, C %A Kollmannsberger, P %D 2020 %J F1000Research %N 1275 %R 10.12688/f1000research.27158.1 %T DeepCLEM: automated registration for correlative light and electron microscopy using deep learning [version 1; peer review: awaiting peer review] %V 9
• Mrestani, A., Kollmannsberger, P., Pauli, M., Repp, F., Kittel, R.J., Eilers, J., Doose, S., Sauer, M., Sir{\’e}n, A.-L., Heckmann, M., Paul, M.M.: Active zone compaction for presynaptic strength. bioRxiv. (2019).
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  Synaptic plasticity is considered to underly information processing and memory formation in the brain and stabilization of neurotransmission during plasticity likely includes reorganization of active zones (AZs).Here, we used localization microscopy and hierarchical density-based spatial clustering to probe AZ architecture at the Drosophila melanogaster neuromuscular junction. We observed distinct arrangements of the scaffold protein Bruchpilot (Brp) at AZs of high release probability type Is and low release probability type Ib boutons. Most remarkably, Brp proteins at type Is AZs were arranged more compact than at type Ib AZs. To ascertain whether adaptations of the AZ scaffold also occur in response to short-term demands, we used philanthotoxin (PhTx) to induce acute homeostatic plasticity. PhTx decreased AZ size, the distance between Brp subclusters and the AZ center, leading to compaction of the Brp scaffold. These changes only occurred at type Ib but not type Is AZs which, already compact, did not undergo structural rearrangement. In summary, our data describe a molecular compaction of the AZ scaffold reflecting the functional demands at high release probability synapses and during an acute homeostasic challenge.

  @article{Mrestani802843, abstract = {Synaptic plasticity is considered to underly information processing and memory formation in the brain and stabilization of neurotransmission during plasticity likely includes reorganization of active zones (AZs).Here, we used localization microscopy and hierarchical density-based spatial clustering to probe AZ architecture at the Drosophila melanogaster neuromuscular junction. We observed distinct arrangements of the scaffold protein Bruchpilot (Brp) at AZs of high release probability type Is and low release probability type Ib boutons. Most remarkably, Brp proteins at type Is AZs were arranged more compact than at type Ib AZs. To ascertain whether adaptations of the AZ scaffold also occur in response to short-term demands, we used philanthotoxin (PhTx) to induce acute homeostatic plasticity. PhTx decreased AZ size, the distance between Brp subclusters and the AZ center, leading to compaction of the Brp scaffold. These changes only occurred at type Ib but not type Is AZs which, already compact, did not undergo structural rearrangement. In summary, our data describe a molecular compaction of the AZ scaffold reflecting the functional demands at high release probability synapses and during an acute homeostasic challenge.}, author = {Mrestani, Achmed and Kollmannsberger, Philip and Pauli, Martin and Repp, Felix and Kittel, Robert J. and Eilers, Jens and Doose, S{\"o}ren and Sauer, Markus and Sir{\'e}n, Anna-Leena and Heckmann, Manfred and Paul, Mila M.}, journal = {bioRxiv}, keywords = {philipkollmannsberger}, publisher = {Cold Spring Harbor Laboratory}, title = {Active zone compaction for presynaptic strength}, year = 2019 }

  %0 Journal Article %1 Mrestani802843 %A Mrestani, Achmed %A Kollmannsberger, Philip %A Pauli, Martin %A Repp, Felix %A Kittel, Robert J. %A Eilers, Jens %A Doose, S{\"o}ren %A Sauer, Markus %A Sir{\'e}n, Anna-Leena %A Heckmann, Manfred %A Paul, Mila M. %D 2019 %I Cold Spring Harbor Laboratory %J bioRxiv %R 10.1101/802843 %T Active zone compaction for presynaptic strength %U https://www.biorxiv.org/content/early/2019/10/13/802843 %X Synaptic plasticity is considered to underly information processing and memory formation in the brain and stabilization of neurotransmission during plasticity likely includes reorganization of active zones (AZs).Here, we used localization microscopy and hierarchical density-based spatial clustering to probe AZ architecture at the Drosophila melanogaster neuromuscular junction. We observed distinct arrangements of the scaffold protein Bruchpilot (Brp) at AZs of high release probability type Is and low release probability type Ib boutons. Most remarkably, Brp proteins at type Is AZs were arranged more compact than at type Ib AZs. To ascertain whether adaptations of the AZ scaffold also occur in response to short-term demands, we used philanthotoxin (PhTx) to induce acute homeostatic plasticity. PhTx decreased AZ size, the distance between Brp subclusters and the AZ center, leading to compaction of the Brp scaffold. These changes only occurred at type Ib but not type Is AZs which, already compact, did not undergo structural rearrangement. In summary, our data describe a molecular compaction of the AZ scaffold reflecting the functional demands at high release probability synapses and during an acute homeostasic challenge.

• Mrestani, A., Pauli, M., Kollmannsberger, P., Repp, F., Kittel, R.J., Eilers, J., Doose, S., Sauer, M., Sirén, A.-L., Heckmann, M., Paul, M.M.: Active zone compaction correlates with presynaptic homeostatic potentiation. Cell Reports. 37, (2021).
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  @article{mrestani_active_2021, author = {Mrestani, Achmed and Pauli, Martin and Kollmannsberger, Philip and Repp, Felix and Kittel, Robert J. and Eilers, Jens and Doose, Sören and Sauer, Markus and Sirén, Anna-Leena and Heckmann, Manfred and Paul, Mila M.}, journal = {Cell Reports}, keywords = {philipkollmannsberger}, month = {oct}, note = {Publisher: Elsevier}, number = 1, title = {Active zone compaction correlates with presynaptic homeostatic potentiation}, volume = 37, year = 2021 }
• Matikonda, S.S., Helmerich, D.A., Meub, M., Beliu, G., Kollmannsberger, P., Greer, A., Sauer, M., Schnermann, M.J.: Defining the {Basis} of {Cyanine} {Phototruncation} {Enables} a {New} {Approach} to {Single}-{Molecule} {Localization} {Microscopy}. ACS Central Science. 7, 1144–1155 (2021).
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  The light-promoted conversion of extensively used cyanine dyes to blue-shifted emissive products has been observed in various contexts. However, both the underlying mechanism and the species involved in this photoconversion reaction have remained elusive. Here we report that irradiation of heptamethine cyanines provides pentamethine cyanines, which, in turn, are photoconverted to trimethine cyanines. We detail an examination of the mechanism and substrate scope of this remarkable two-carbon phototruncation reaction. Supported by computational analysis, we propose that this reaction involves a singlet oxygen-initiated multistep sequence involving a key hydroperoxycyclobutanol intermediate. Building on this mechanistic framework, we identify conditions to improve the yield of photoconversion by over an order of magnitude. We then demonstrate that cyanine phototruncation can be applied to super-resolution single-molecule localization microscopy, leading to improved spatial resolution with shorter imaging times. We anticipate these insights will help transform a common, but previously mechanistically ill-defined, chemical transformation into a valuable optical tool.

  @article{matikonda_defining_2021, abstract = {The light-promoted conversion of extensively used cyanine dyes to blue-shifted emissive products has been observed in various contexts. However, both the underlying mechanism and the species involved in this photoconversion reaction have remained elusive. Here we report that irradiation of heptamethine cyanines provides pentamethine cyanines, which, in turn, are photoconverted to trimethine cyanines. We detail an examination of the mechanism and substrate scope of this remarkable two-carbon phototruncation reaction. Supported by computational analysis, we propose that this reaction involves a singlet oxygen-initiated multistep sequence involving a key hydroperoxycyclobutanol intermediate. Building on this mechanistic framework, we identify conditions to improve the yield of photoconversion by over an order of magnitude. We then demonstrate that cyanine phototruncation can be applied to super-resolution single-molecule localization microscopy, leading to improved spatial resolution with shorter imaging times. We anticipate these insights will help transform a common, but previously mechanistically ill-defined, chemical transformation into a valuable optical tool.}, author = {Matikonda, Siddharth S. and Helmerich, Dominic A. and Meub, Mara and Beliu, Gerti and Kollmannsberger, Philip and Greer, Alexander and Sauer, Markus and Schnermann, Martin J.}, journal = {ACS Central Science}, keywords = {philipkollmannsberger}, month = {jul}, note = {Publisher: American Chemical Society}, number = 7, pages = {1144–1155}, title = {Defining the {Basis} of {Cyanine} {Phototruncation} {Enables} a {New} {Approach} to {Single}-{Molecule} {Localization} {Microscopy}}, volume = 7, year = 2021 }
• Marquardt, A., Solimando, A.G., Kerscher, A., Bittrich, M., Kalogirou, C., Kübler, H., Rosenwald, A., Bargou, R., Kollmannsberger, P., Schilling, B., Meierjohann, S., Krebs, M.: Subgroup-{Independent} {Mapping} of {Renal} {Cell} {Carcinoma}—{Machine} {Learning} {Reveals} {Prognostic} {Mitochondrial} {Gene} {Signature} {Beyond} {Histopathologic} {Boundaries}. Frontiers in Oncology. 11, (2021).
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  Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups—clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups., Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256)., Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin (mixed subgroup)—demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature—a trait previously known for chRCC—across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC—and a highly significant longer overall survival for chRCC patients., Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment.

  @article{marquardt_subgroup-independent_2021, abstract = {Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups—clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups., Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256)., Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin (mixed subgroup)—demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature—a trait previously known for chRCC—across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC—and a highly significant longer overall survival for chRCC patients., Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment.}, author = {Marquardt, André and Solimando, Antonio Giovanni and Kerscher, Alexander and Bittrich, Max and Kalogirou, Charis and Kübler, Hubert and Rosenwald, Andreas and Bargou, Ralf and Kollmannsberger, Philip and Schilling, Bastian and Meierjohann, Svenja and Krebs, Markus}, journal = {Frontiers in Oncology}, keywords = {philipkollmannsberger}, month = {mar}, title = {Subgroup-{Independent} {Mapping} of {Renal} {Cell} {Carcinoma}—{Machine} {Learning} {Reveals} {Prognostic} {Mitochondrial} {Gene} {Signature} {Beyond} {Histopathologic} {Boundaries}}, volume = 11, year = 2021 }
• Pauli, M., Paul, M.M., Proppert, S., Mrestani, A., Sharifi, M., Repp, F., Kürzinger, L., Kollmannsberger, P., Sauer, M., Heckmann, M., Sirén, A.-L.: Targeted volumetric single-molecule localization microscopy of defined presynaptic structures in brain sections. Communications Biology. 4, 1–13 (2021).
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  Revealing the molecular organization of anatomically precisely defined brain regions is necessary for refined understanding of synaptic plasticity. Although three-dimensional (3D) single-molecule localization microscopy can provide the required resolution, imaging more than a few micrometers deep into tissue remains challenging. To quantify presynaptic active zones (AZ) of entire, large, conditional detonator hippocampal mossy fiber (MF) boutons with diameters as large as 10 µm, we developed a method for targeted volumetric direct stochastic optical reconstruction microscopy (dSTORM). An optimized protocol for fast repeated axial scanning and efficient sequential labeling of the AZ scaffold Bassoon and membrane bound GFP with Alexa Fluor 647 enabled 3D-dSTORM imaging of 25 µm thick mouse brain sections and assignment of AZs to specific neuronal substructures. Quantitative data analysis revealed large differences in Bassoon cluster size and density for distinct hippocampal regions with largest clusters in MF boutons.

  @article{pauli_targeted_2021, abstract = {Revealing the molecular organization of anatomically precisely defined brain regions is necessary for refined understanding of synaptic plasticity. Although three-dimensional (3D) single-molecule localization microscopy can provide the required resolution, imaging more than a few micrometers deep into tissue remains challenging. To quantify presynaptic active zones (AZ) of entire, large, conditional detonator hippocampal mossy fiber (MF) boutons with diameters as large as 10 µm, we developed a method for targeted volumetric direct stochastic optical reconstruction microscopy (dSTORM). An optimized protocol for fast repeated axial scanning and efficient sequential labeling of the AZ scaffold Bassoon and membrane bound GFP with Alexa Fluor 647 enabled 3D-dSTORM imaging of 25 µm thick mouse brain sections and assignment of AZs to specific neuronal substructures. Quantitative data analysis revealed large differences in Bassoon cluster size and density for distinct hippocampal regions with largest clusters in MF boutons.}, author = {Pauli, Martin and Paul, Mila M. and Proppert, Sven and Mrestani, Achmed and Sharifi, Marzieh and Repp, Felix and Kürzinger, Lydia and Kollmannsberger, Philip and Sauer, Markus and Heckmann, Manfred and Sirén, Anna-Leena}, journal = {Communications Biology}, keywords = {philipkollmannsberger}, month = {mar}, note = {Number: 1Publisher: Nature Publishing Group}, number = 1, pages = {1–13}, title = {Targeted volumetric single-molecule localization microscopy of defined presynaptic structures in brain sections}, volume = 4, year = 2021 }
• Marquardt, A., Landwehr, L.-S., Ronchi, C.L., di Dalmazi, G., Riester, A., Kollmannsberger, P., Altieri, B., Fassnacht, M., Sbiera, S.: Identifying {New} {Potential} {Biomarkers} in {Adrenocortical} {Tumors} {Based} on {mRNA} {Expression} {Data} {Using} {Machine} {Learning}. Cancers. 13, 4671 (2021).
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  Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC.

  @article{marquardt_identifying_2021, abstract = {Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC.}, author = {Marquardt, André and Landwehr, Laura-Sophie and Ronchi, Cristina L. and di Dalmazi, Guido and Riester, Anna and Kollmannsberger, Philip and Altieri, Barbara and Fassnacht, Martin and Sbiera, Silviu}, journal = {Cancers}, keywords = {philipkollmannsberger}, month = {jan}, note = {Number: 18Publisher: Multidisciplinary Digital Publishing Institute}, number = 18, pages = 4671, title = {Identifying {New} {Potential} {Biomarkers} in {Adrenocortical} {Tumors} {Based} on {mRNA} {Expression} {Data} {Using} {Machine} {Learning}}, volume = 13, year = 2021 }

• Mostosi, P., Schindelin, H., Kollmannsberger, P., Thorn, A.: Haruspex: {A} {Neural} {Network} for the {Automatic} {Identification} of {Oligonucleotides} and {Protein} {Secondary} {Structure} in {Cryo}-{Electron} {Microscopy} {Maps}. Angewandte Chemie International Edition. n/a, (2020).
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  In recent years, three-dimensional density maps reconstructed from single particle images obtained by electron cryo-microscopy (cryo-EM) have reached unprecedented resolution. However, map interpretation can be challenging, in particular if the constituting structures require de-novo model building or are very mobile. Herein, we demonstrate the potential of convolutional neural networks for the annotation of cryo-EM maps: our network Haruspex has been trained on a carefully curated set of 293 experimentally derived reconstruction maps to automatically annotate RNA/DNA as well as protein secondary structure elements. It can be straightforwardly applied to newly reconstructed maps in order to support domain placement or as a starting point for main-chain placement. Due to its high recall and precision rates of 95.1 \% and 80.3 \%, respectively, on an independent test set of 122 maps, it can also be used for validation during model building. The trained network will be available as part of the CCP-EM suite.

  @article{mostosi_haruspex_nodate, abstract = {In recent years, three-dimensional density maps reconstructed from single particle images obtained by electron cryo-microscopy (cryo-EM) have reached unprecedented resolution. However, map interpretation can be challenging, in particular if the constituting structures require de-novo model building or are very mobile. Herein, we demonstrate the potential of convolutional neural networks for the annotation of cryo-EM maps: our network Haruspex has been trained on a carefully curated set of 293 experimentally derived reconstruction maps to automatically annotate RNA/DNA as well as protein secondary structure elements. It can be straightforwardly applied to newly reconstructed maps in order to support domain placement or as a starting point for main-chain placement. Due to its high recall and precision rates of 95.1 \% and 80.3 \%, respectively, on an independent test set of 122 maps, it can also be used for validation during model building. The trained network will be available as part of the CCP-EM suite.}, author = {Mostosi, Philipp and Schindelin, Hermann and Kollmannsberger, Philip and Thorn, Andrea}, journal = {Angewandte Chemie International Edition}, keywords = {philipkollmannsberger}, note = {\_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.202000421}, number = {n/a}, title = {Haruspex: {A} {Neural} {Network} for the {Automatic} {Identification} of {Oligonucleotides} and {Protein} {Secondary} {Structure} in {Cryo}-{Electron} {Microscopy} {Maps}}, volume = {n/a}, year = 2020 }
• Paul, T.J., Kollmannsberger, P.: Biological network growth in complex environments – a computational framework. PLOS Computational Biology. 16, e1008003 (2020).
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  {\textless}p{\textgreater}Spatial biological networks are abundant on all scales of life, from single cells to ecosystems, and perform various important functions including signal transmission and nutrient transport. These biological functions depend on the architecture of the network, which emerges as the result of a dynamic, feedback-driven developmental process. While cell behavior during growth can be genetically encoded, the resulting network structure depends on spatial constraints and tissue architecture. Since network growth is often difficult to observe experimentally, computer simulations can help to understand how local cell behavior determines the resulting network architecture. We present here a computational framework based on directional statistics to model network formation in space and time under arbitrary spatial constraints. Growth is described as a biased correlated random walk where direction and branching depend on the local environmental conditions and constraints, which are presented as 3D multilayer images. To demonstrate the application of our tool, we perform growth simulations of the osteocyte lacuno-canalicular system in bone and of the zebrafish sensory nervous system. Our generic framework might help to better understand how network patterns depend on spatial constraints, or to identify the biological cause of deviations from healthy network function.{\textless}/p{\textgreater}

  @article{paul_biological_2020, abstract = {{\textless}p{\textgreater}Spatial biological networks are abundant on all scales of life, from single cells to ecosystems, and perform various important functions including signal transmission and nutrient transport. These biological functions depend on the architecture of the network, which emerges as the result of a dynamic, feedback-driven developmental process. While cell behavior during growth can be genetically encoded, the resulting network structure depends on spatial constraints and tissue architecture. Since network growth is often difficult to observe experimentally, computer simulations can help to understand how local cell behavior determines the resulting network architecture. We present here a computational framework based on directional statistics to model network formation in space and time under arbitrary spatial constraints. Growth is described as a biased correlated random walk where direction and branching depend on the local environmental conditions and constraints, which are presented as 3D multilayer images. To demonstrate the application of our tool, we perform growth simulations of the osteocyte lacuno-canalicular system in bone and of the zebrafish sensory nervous system. Our generic framework might help to better understand how network patterns depend on spatial constraints, or to identify the biological cause of deviations from healthy network function.{\textless}/p{\textgreater}}, author = {Paul, Torsten Johann and Kollmannsberger, Philip}, journal = {PLOS Computational Biology}, keywords = {philipkollmannsberger}, number = 11, pages = {e1008003}, title = {Biological network growth in complex environments – a computational framework}, volume = 16, year = 2020 }
• Sahlol, A.T., Kollmannsberger, P., Ewees, A.A.: Efficient {Classification} of {White} {Blood} {Cell} {Leukemia} with {Improved} {Swarm} {Optimization} of {Deep} {Features}. Scientific Reports. 10, 2536 (2020).
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  White Blood Cell (WBC) Leukaemia is caused by excessive production of leukocytes in the bone marrow, and image-based detection of malignant WBCs is important for its detection. Convolutional Neural Networks (CNNs) present the current state-of-the-art for this type of image classification, but their computational cost for training and deployment can be high. We here present an improved hybrid approach for efficient classification of WBC Leukemia. We first extract features from WBC images using VGGNet, a powerful CNN architecture, pre-trained on ImageNet. The extracted features are then filtered using a statistically enhanced Salp Swarm Algorithm (SESSA). This bio-inspired optimization algorithm selects the most relevant features and removes highly correlated and noisy features. We applied the proposed approach to two public WBC Leukemia reference datasets and achieve both high accuracy and reduced computational complexity. The SESSA optimization selected only 1 K out of 25 K features extracted with VGGNet, while improving accuracy at the same time. The results are among the best achieved on these datasets and outperform several convolutional network models. We expect that the combination of CNN feature extraction and SESSA feature optimization could be useful for many other image classification tasks.

  @article{sahlol_efficient_2020, abstract = {White Blood Cell (WBC) Leukaemia is caused by excessive production of leukocytes in the bone marrow, and image-based detection of malignant WBCs is important for its detection. Convolutional Neural Networks (CNNs) present the current state-of-the-art for this type of image classification, but their computational cost for training and deployment can be high. We here present an improved hybrid approach for efficient classification of WBC Leukemia. We first extract features from WBC images using VGGNet, a powerful CNN architecture, pre-trained on ImageNet. The extracted features are then filtered using a statistically enhanced Salp Swarm Algorithm (SESSA). This bio-inspired optimization algorithm selects the most relevant features and removes highly correlated and noisy features. We applied the proposed approach to two public WBC Leukemia reference datasets and achieve both high accuracy and reduced computational complexity. The SESSA optimization selected only 1 K out of 25 K features extracted with VGGNet, while improving accuracy at the same time. The results are among the best achieved on these datasets and outperform several convolutional network models. We expect that the combination of CNN feature extraction and SESSA feature optimization could be useful for many other image classification tasks.}, author = {Sahlol, Ahmed T. and Kollmannsberger, Philip and Ewees, Ahmed A.}, journal = {Scientific Reports}, keywords = {philipkollmannsberger}, month = {feb}, note = {Number: 1Publisher: Nature Publishing Group}, number = 1, pages = 2536, title = {Efficient {Classification} of {White} {Blood} {Cell} {Leukemia} with {Improved} {Swarm} {Optimization} of {Deep} {Features}}, volume = 10, year = 2020 }

• Spindler, M.-C., Redolfi, J., Helmprobst, F., Kollmannsberger, P., Stigloher, C., Benavente, R.: Electron tomography of mouse LINC complexes at meiotic telomere attachment sites with and without microtubules. Communications Biology. 2, 376- (2019).
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  Telomere movements during meiotic prophase I facilitate synapsis and recombination of homologous chromosomes. Hereby, chromosome movements depend on the dynamic attachment of meiotic telomeres to the nuclear envelope and generation of forces that actively move the telomeres. In most eukaryotes, forces that move telomeres are generated in the cytoplasm by microtubule-associated motor proteins and transduced into the nucleus through the LINC complexes of the nuclear envelope. Meiotic LINC complexes, in mouse comprised of SUN1/2 and KASH5, selectively localize to the attachment sites of meiotic telomeres. For a better understanding of meiotic telomere dynamics, here we provide quantitative information of telomere attachment sites that we have generated with the aid of electron microscope tomography (EM tomography). Our data on the number, length, width, distribution and relation with microtubules of the reconstructed structures indicate that an average number of 76 LINC complexes would be required to move a telomere attachment site.

  @article{spindler2019electron, abstract = {Telomere movements during meiotic prophase I facilitate synapsis and recombination of homologous chromosomes. Hereby, chromosome movements depend on the dynamic attachment of meiotic telomeres to the nuclear envelope and generation of forces that actively move the telomeres. In most eukaryotes, forces that move telomeres are generated in the cytoplasm by microtubule-associated motor proteins and transduced into the nucleus through the LINC complexes of the nuclear envelope. Meiotic LINC complexes, in mouse comprised of SUN1/2 and KASH5, selectively localize to the attachment sites of meiotic telomeres. For a better understanding of meiotic telomere dynamics, here we provide quantitative information of telomere attachment sites that we have generated with the aid of electron microscope tomography (EM tomography). Our data on the number, length, width, distribution and relation with microtubules of the reconstructed structures indicate that an average number of 76 LINC complexes would be required to move a telomere attachment site.}, author = {Spindler, Marie-Christin and Redolfi, Josef and Helmprobst, Frederik and Kollmannsberger, Philip and Stigloher, Christian and Benavente, Ricardo}, journal = {Communications Biology}, keywords = {philipkollmannsberger}, number = 1, pages = {376–}, title = {Electron tomography of mouse LINC complexes at meiotic telomere attachment sites with and without microtubules}, volume = 2, year = 2019 }
• Ehrig, S., Bidan, C.M., West, A., Jacobi, C., Lam, K., Kollmannsberger, P., Petersen, A., Tomancak, P., Kommareddy, K., Fischer, F.D., Fratzl, P., Dunlop, J.W.C.: Surface tension determines tissue shape and growth kinetics. Science Advances. 5, eaav9394 (2019).
  • [ Abstract ]
  • [ BibTeX ]
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  • [ DOI ]
  The growth of tissue is an essential process controlling morphogenesis and regeneration of organs. In general tissue forming cells are interactive and motile, which can give rise to emergent physical properties such as viscous fluid behaviour as has been shown for epithelial monolayers during embryogenesis, and for cell-agglomerates with a measurable surface tension. However, the mechanical integrity of tissues is provided by extracellular matrices (ECM) that turn tissues into solids with well-defined elastic properties. Paradoxically, it has been shown by in-vitro experiments that even osteoid-like tissue with large amounts of ECM grows according to rules reminiscent of fluid behavior. Motivated by this conundrum, we show here quantitatively, by constraining growing tissues to surfaces of controlled mean curvature, that osteoid-like tissues, develop shapes similar to the equilibrium shapes of fluids. In particular, for geometries with rotational symmetry, the tissue stays bounded by Delaunay surfaces and grows with rates depending on surface curvature. Actin stress-fibre patterns at the tissue surface suggests that cell contractility is responsible for generating the necessary surface stresses. This indicates that continuous remodeling of the solid matrix combined with the contractility of bone forming cells provide sufficient effective fluidity and surface stress required for a fluid-like behavior of the growing tissue at the time scale of days to weeks. Our work demonstrates that morphogenesis shares fundamental physical principles with fluid droplets as first suggested in D'Arcy Thompson's seminal work 'On Growth and Form'.

  @article{ehrig_surface_2018, abstract = {The growth of tissue is an essential process controlling morphogenesis and regeneration of organs. In general tissue forming cells are interactive and motile, which can give rise to emergent physical properties such as viscous fluid behaviour as has been shown for epithelial monolayers during embryogenesis, and for cell-agglomerates with a measurable surface tension. However, the mechanical integrity of tissues is provided by extracellular matrices (ECM) that turn tissues into solids with well-defined elastic properties. Paradoxically, it has been shown by in-vitro experiments that even osteoid-like tissue with large amounts of ECM grows according to rules reminiscent of fluid behavior. Motivated by this conundrum, we show here quantitatively, by constraining growing tissues to surfaces of controlled mean curvature, that osteoid-like tissues, develop shapes similar to the equilibrium shapes of fluids. In particular, for geometries with rotational symmetry, the tissue stays bounded by Delaunay surfaces and grows with rates depending on surface curvature. Actin stress-fibre patterns at the tissue surface suggests that cell contractility is responsible for generating the necessary surface stresses. This indicates that continuous remodeling of the solid matrix combined with the contractility of bone forming cells provide sufficient effective fluidity and surface stress required for a fluid-like behavior of the growing tissue at the time scale of days to weeks. Our work demonstrates that morphogenesis shares fundamental physical principles with fluid droplets as first suggested in D'Arcy Thompson's seminal work 'On Growth and Form'.}, author = {Ehrig, Sebastian and Bidan, Cécile M. and West, Alan and Jacobi, Cornelius and Lam, Karen and Kollmannsberger, Philip and Petersen, Ansgar and Tomancak, Pavel and Kommareddy, Krishna and Fischer, Franz Dieter and Fratzl, Peter and Dunlop, John W. C.}, journal = {Science Advances}, keywords = {philipkollmannsberger}, number = 9, pages = {eaav9394}, title = {Surface tension determines tissue shape and growth kinetics}, volume = 5, year = 2019 }
• Weinkamer, R., Kollmannsberger, P., Fratzl, P.: Towards a {Connectomic} {Description} of the {Osteocyte} {Lacunocanalicular} {Network} in {Bone}. Current Osteoporosis Reports. (2019).
  • [ Abstract ]
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  Purpose of ReviewOsteocytes are the most abundant bone cells. They are completely encased in mineralized tissue, sitting inside lacunae that are connected by a multitude of canaliculi. In recent years, the osteocyte network has been shown to fulfill endocrine functions and to communicate with a number of other organs. This review addresses emerging knowledge on the connectome of the lacunocanalicular network in different types of bone tissue.Recent FindingsRecent advances in three-dimensional imaging technology started to reveal parameters that are well known from general theory to characterize the function of networks, such as network density, degree of nodes, or shortest path length through the network.SummaryThe connectome of the lacunocanalicular network differs in some aspects between lamellar and woven bone and seems to change with age. More research is needed to relate network structure to function, such as intercellular transport or communication and its role in mechanosensation, as well as to understand the effect of diseases.

  @article{weinkamer_towards_2019, abstract = {Purpose of ReviewOsteocytes are the most abundant bone cells. They are completely encased in mineralized tissue, sitting inside lacunae that are connected by a multitude of canaliculi. In recent years, the osteocyte network has been shown to fulfill endocrine functions and to communicate with a number of other organs. This review addresses emerging knowledge on the connectome of the lacunocanalicular network in different types of bone tissue.Recent FindingsRecent advances in three-dimensional imaging technology started to reveal parameters that are well known from general theory to characterize the function of networks, such as network density, degree of nodes, or shortest path length through the network.SummaryThe connectome of the lacunocanalicular network differs in some aspects between lamellar and woven bone and seems to change with age. More research is needed to relate network structure to function, such as intercellular transport or communication and its role in mechanosensation, as well as to understand the effect of diseases.}, author = {Weinkamer, Richard and Kollmannsberger, Philip and Fratzl, Peter}, journal = {Current Osteoporosis Reports}, keywords = {philipkollmannsberger}, month = {may}, title = {Towards a {Connectomic} {Description} of the {Osteocyte} {Lacunocanalicular} {Network} in {Bone}}, year = 2019 }

• Kaltdorf, K.V., Theiss, M., Markert, S.M., Zhen, M., Dandekar, T., Stigloher, C., Kollmannsberger, P.: Automated classification of synaptic vesicles in electron tomograms of C. elegans using machine learning. PLoS one. 13, e0205348 (2018).
  • [ Abstract ]
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  Synaptic vesicles (SVs) are a key component of neuronal signaling and fulfil different roles depending on their composition. In electron micrograms of neurites, two types of vesicles can be distinguished by morphological criteria, the classical "clear core" vesicles (CCV) and the typically larger "dense core" vesicles (DCV), with differences in electron density due to their diverse cargos. Compared to CCVs, the precise function of DCVs is less defined. DCVs are known to store neuropeptides, which function as neuronal messengers and modulators. In C. elegans, they play a role in locomotion, dauer formation, egg-laying, and mechano- and chemosensation. Another type of DCVs, also referred to as granulated vesicles, are known to transport Bassoon, Piccolo and further constituents of the presynaptic density in the center of the active zone (AZ), and therefore are important for synaptogenesis. To better understand the role of different types of SVs, we present here a new automated approach to classify vesicles. We combine machine learning with an extension of our previously developed vesicle segmentation workflow, the ImageJ macro 3D ART VeSElecT. With that we reliably distinguish CCVs and DCVs in electron tomograms of C. elegans NMJs using image-based features. Analysis of the underlying ground truth data shows an increased fraction of DCVs as well as a higher mean distance between DCVs and AZs in dauer larvae compared to young adult hermaphrodites. Our machine learning based tools are adaptable and can be applied to study properties of different synaptic vesicle pools in electron tomograms of diverse model organisms.

  @article{Kaltdorf291310, abstract = {Synaptic vesicles (SVs) are a key component of neuronal signaling and fulfil different roles depending on their composition. In electron micrograms of neurites, two types of vesicles can be distinguished by morphological criteria, the classical "clear core" vesicles (CCV) and the typically larger "dense core" vesicles (DCV), with differences in electron density due to their diverse cargos. Compared to CCVs, the precise function of DCVs is less defined. DCVs are known to store neuropeptides, which function as neuronal messengers and modulators. In C. elegans, they play a role in locomotion, dauer formation, egg-laying, and mechano- and chemosensation. Another type of DCVs, also referred to as granulated vesicles, are known to transport Bassoon, Piccolo and further constituents of the presynaptic density in the center of the active zone (AZ), and therefore are important for synaptogenesis. To better understand the role of different types of SVs, we present here a new automated approach to classify vesicles. We combine machine learning with an extension of our previously developed vesicle segmentation workflow, the ImageJ macro 3D ART VeSElecT. With that we reliably distinguish CCVs and DCVs in electron tomograms of C. elegans NMJs using image-based features. Analysis of the underlying ground truth data shows an increased fraction of DCVs as well as a higher mean distance between DCVs and AZs in dauer larvae compared to young adult hermaphrodites. Our machine learning based tools are adaptable and can be applied to study properties of different synaptic vesicle pools in electron tomograms of diverse model organisms.}, author = {Kaltdorf, Kristin V and Theiss, Maria and Markert, Sebastian M and Zhen, Mei and Dandekar, Thomas and Stigloher, Christian and Kollmannsberger, Philip}, journal = {PLoS one}, keywords = {philipkollmannsberger}, number = 10, pages = {e0205348}, publisher = {Public Library of Science}, title = {Automated classification of synaptic vesicles in electron tomograms of C. elegans using machine learning}, volume = 13, year = 2018 }
• Kollmannsberger, P., Bidan, C.M., Dunlop, J., Fratzl, P., Vogel, V.: Tensile forces drive a reversible fibroblast-to-myofibroblast transition during tissue growth in engineered clefts. Science Advances. 4, eaao4881 (2018).
  • [ BibTeX ]
  • [ DOI ]
  @article{kollmannsberger2018tensile, author = {Kollmannsberger, Philip and Bidan, Cécile M and Dunlop, John and Fratzl, Peter and Vogel, Viola}, journal = {Science Advances}, keywords = {philipkollmannsberger}, number = 1, pages = {eaao4881}, title = {Tensile forces drive a reversible fibroblast-to-myofibroblast transition during tissue growth in engineered clefts}, volume = 4, year = 2018 }

• Repp, F., Kollmannsberger, P., Roschger, A., Berzlanovich, A., Gruber, G., Roschger, P., Wagermaier, W., Weinkamer, R.: Coalignment of osteocyte canaliculi and collagen fibers in human osteonal bone. Journal of Stuctural Biology. 199, 177–186 (2017).
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  • [ DOI ]
  @article{repp2017coalignment, author = {Repp, Felix and Kollmannsberger, Philip and Roschger, Andreas and Berzlanovich, Andrea and Gruber, Gerlinde and Roschger, Paul and Wagermaier, Wolfgang and Weinkamer, Richard}, journal = {Journal of Stuctural Biology}, keywords = {philipkollmannsberger}, pages = {177-186}, title = {Coalignment of osteocyte canaliculi and collagen fibers in human osteonal bone}, volume = 199, year = 2017 }
• Repp, F., Kollmannsberger, P., Roschger, A., Kerschnitzki, M., Berzlanovich, A., Gruber, G.M., Roschger, P., Wagermaier, W., Weinkamer, R.: Spatial heterogeneity in the canalicular density of the osteocyte network in human osteons. Bone Reports. 6, 101–108 (2017).
  • [ BibTeX ]
  @article{repp2017spatial, author = {Repp, Felix and Kollmannsberger, Philip and Roschger, Andreas and Kerschnitzki, Michael and Berzlanovich, Andrea and Gruber, Gerlinde M. and Roschger, Paul and Wagermaier, Wolfgang and Weinkamer, Richard}, journal = {Bone Reports}, keywords = {philipkollmannsberger}, pages = {101-108}, title = {Spatial heterogeneity in the canalicular density of the osteocyte network in human osteons}, volume = 6, year = 2017 }
• Kollmannsberger, P., Kerschnitzki, M., Repp, F., Wagermaier, W., Weinkamer, R., Fratzl, P.: The Small World of Osteocytes: Connectomics of the Lacuno-Canalicular Network in Bone. New Journal of Physics. 19, 073019 (2017).
  • [ Abstract ]
  • [ BibTeX ]
  Osteocytes and their cell processes reside in a large, interconnected network of voids pervading the mineralized bone matrix of most vertebrates. This osteocyte lacuno-canalicular network (OLCN) is believed to play important roles in mechanosensing, mineral homeostasis, and for the mechanical properties of bone. While the extracellular matrix structure of bone is extensively studied on ultrastructural and macroscopic scales, there is a lack of quantitative knowledge on how the cellular network is organized. Using a recently introduced imaging and quantification approach, we analyze the OLCN in different bone types from mouse and sheep that exhibit different degrees of structural organization not only of the cell network but also of the fibrous matrix deposited by the cells. We define a number of robust, quantitative measures that are derived from the theory of complex networks. These measures enable us to gain insights into how efficient the network is organized with regard to intercellular transport and communication. Our analysis shows that the cell network in regularly organized, slow-growing bone tissue from sheep is less connected, but more efficiently organized compared to irregular and fast-growing bone tissue from mice. On the level of statistical topological properties (edges per node, edge length and degree distribution), both network types are indistinguishable, highlighting that despite pronounced differences at the tissue level, the topological architecture of the osteocyte canalicular network at the subcellular level may be independent of species and bone type. Our results suggest a universal mechanism underlying the self-organization of individual cells into a large, interconnected network during bone formation and mineralization.

  @article{kollmannsberger2017small, abstract = {Osteocytes and their cell processes reside in a large, interconnected network of voids pervading the mineralized bone matrix of most vertebrates. This osteocyte lacuno-canalicular network (OLCN) is believed to play important roles in mechanosensing, mineral homeostasis, and for the mechanical properties of bone. While the extracellular matrix structure of bone is extensively studied on ultrastructural and macroscopic scales, there is a lack of quantitative knowledge on how the cellular network is organized. Using a recently introduced imaging and quantification approach, we analyze the OLCN in different bone types from mouse and sheep that exhibit different degrees of structural organization not only of the cell network but also of the fibrous matrix deposited by the cells. We define a number of robust, quantitative measures that are derived from the theory of complex networks. These measures enable us to gain insights into how efficient the network is organized with regard to intercellular transport and communication. Our analysis shows that the cell network in regularly organized, slow-growing bone tissue from sheep is less connected, but more efficiently organized compared to irregular and fast-growing bone tissue from mice. On the level of statistical topological properties (edges per node, edge length and degree distribution), both network types are indistinguishable, highlighting that despite pronounced differences at the tissue level, the topological architecture of the osteocyte canalicular network at the subcellular level may be independent of species and bone type. Our results suggest a universal mechanism underlying the self-organization of individual cells into a large, interconnected network during bone formation and mineralization.}, author = {Kollmannsberger, Philip and Kerschnitzki, Michael and Repp, Felix and Wagermaier, Wolfgang and Weinkamer, Richard and Fratzl, Peter}, journal = {New Journal of Physics}, keywords = {philipkollmannsberger}, pages = {073019}, title = {The Small World of Osteocytes: Connectomics of the Lacuno-Canalicular Network in Bone.}, type = {Publication}, volume = 19, year = 2017 }
• Kaltdorf, K.V., Schulze, K., Helmprobst, F., Kollmannsberger, P., Dandekar, T., Stigloher, C.: FIJI Macro 3D ART VeSElecT: 3D Automated Reconstruction Tool for Vesicle Structures of Electron Tomograms. PLOS Computational Biology. 13, 1–21 (2017).
  • [ Abstract ]
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  • [ URL ]
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  Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation. Both automatic and semi-automatic modes are explained including a tutorial.

  @article{10.1371/journal.pcbi.1005317, abstract = {Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation. Both automatic and semi-automatic modes are explained including a tutorial.}, author = {Kaltdorf, Kristin Verena and Schulze, Katja and Helmprobst, Frederik and Kollmannsberger, Philip and Dandekar, Thomas and Stigloher, Christian}, journal = {PLOS Computational Biology}, keywords = {philipkollmannsberger}, month = {01}, number = 1, pages = {1-21}, publisher = {Public Library of Science}, title = {FIJI Macro 3D ART VeSElecT: 3D Automated Reconstruction Tool for Vesicle Structures of Electron Tomograms}, volume = 13, year = 2017 }

• Bidan, C.M., Kollmannsberger, P., Gering, V., Ehrig, S., Joly, P., Petersen, A., Vogel, V., Fratzl, P., Dunlop, J.W.C.: Gradual conversion of cellular stress patterns into pre-stressed matrix architecture during in vitro tissue growth. Journal of The Royal Society Interface. 13, (2016).
  • [ Abstract ]
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  The complex arrangement of the extracellular matrix (ECM) produced by cells during tissue growth, healing and remodelling is fundamental to tissue function. In connective tissues, it is still unclear how both cells and the ECM become and remain organized over length scales much larger than the distance between neighbouring cells. While cytoskeletal forces are essential for assembly and organization of the early ECM, how these processes lead to a highly organized ECM in tissues such as osteoid is not clear. To clarify the role of cellular tension for the development of these ordered fibril architectures, we used an in vitro model system, where pre-osteoblastic cells produced ECM-rich tissue inside channels with millimetre-sized triangular cross sections in ceramic scaffolds. Our results suggest a mechanical handshake between actively contracting cells and ECM fibrils: the build-up of a long-range organization of cells and the ECM enables a gradual conversion of cell-generated tension to pre-straining the ECM fibrils, which reduces the work cells have to generate to keep mature tissue under tension.

  @article{Bidan20160136, abstract = {The complex arrangement of the extracellular matrix (ECM) produced by cells during tissue growth, healing and remodelling is fundamental to tissue function. In connective tissues, it is still unclear how both cells and the ECM become and remain organized over length scales much larger than the distance between neighbouring cells. While cytoskeletal forces are essential for assembly and organization of the early ECM, how these processes lead to a highly organized ECM in tissues such as osteoid is not clear. To clarify the role of cellular tension for the development of these ordered fibril architectures, we used an in vitro model system, where pre-osteoblastic cells produced ECM-rich tissue inside channels with millimetre-sized triangular cross sections in ceramic scaffolds. Our results suggest a mechanical handshake between actively contracting cells and ECM fibrils: the build-up of a long-range organization of cells and the ECM enables a gradual conversion of cell-generated tension to pre-straining the ECM fibrils, which reduces the work cells have to generate to keep mature tissue under tension.}, author = {Bidan, C{\'e}cile M. and Kollmannsberger, Philip and Gering, Vanessa and Ehrig, Sebastian and Joly, Pascal and Petersen, Ansgar and Vogel, Viola and Fratzl, Peter and Dunlop, John W. C.}, journal = {Journal of The Royal Society Interface}, keywords = {myown}, number = 118, publisher = {The Royal Society}, title = {Gradual conversion of cellular stress patterns into pre-stressed matrix architecture during in vitro tissue growth}, volume = 13, year = 2016 }
• Yamashita, T., Kollmannsberger, P., Mawatari, K., Kitamori, T., Vogel, V.: Cell sheet mechanics: How geometrical constraints induce the detachment of cell sheets from concave surfaces. Acta Biomaterialia. 45, 85–97 (2016).
  • [ Abstract ]
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  • [ URL ]
  • [ DOI ]
  Abstract Despite of the progress made to engineer structured microtissues such as BioMEMS and 3D bioprinting, little control exists how microtissues transform as they mature, as the misbalance between cell-generated forces and the strength of cell-cell and cell-substrate contacts can result in unintended tissue deformations and ruptures. To develop a quantitative perspective on how cellular contractility, scaffold curvature and cell-substrate adhesion control such rupture processes, human aortic smooth muscle cells were grown on glass substrates with submillimeter semichannels. We quantified cell sheet detachment from 3D confocal image stacks as a function of channel curvature and cell sheet tension by adding different amounts of Blebbistatin and TGF-β to inhibit or enhance cell contractility, respectively. We found that both higher curvature and higher contractility increased the detachment probability. Variations of the adhesive strength of the protein coating on the substrate revealed that the rupture plane was localized along the substrate-extracellular matrix interface for non-covalently adsorbed adhesion proteins, while the collagen-integrin interface ruptured when collagen I was covalently crosslinked to the substrate. Finally, a simple mechanical model is introduced that quantitatively explains how the tuning of substrate curvature, cell sheet contractility and adhesive strength can be used as tunable parameters as summarized in a first semi-quantitative phase diagram. These parameters can thus be exploited to either inhibit or purposefully induce a collective detachment of sheet-like microtissues for the use in tissue engineering and regenerative therapies. Statement of Significance Despite of the significant progress in 3D tissue fabrication technologies at the microscale, there is still no quantitative model that can predict if cells seeded on a 3D structure maintain the imposed geometry while they form a continuous microtissue. Especially, detachment or loss of shape control of growing tissue is a major concern when designing 3D-structured scaffolds. Utilizing semi-cylindrical channels and vascular smooth muscle cells, we characterized how geometrical and mechanical parameters such as curvature of the substrate, cellular contractility, or protein-substrate adhesion strength tune the catastrophic detachment of microtissue. Observed results were rationalized by a theoretical model. The phase diagram showing how unintended tissue detachment progresses would help in designing of mechanically-balanced 3D scaffolds in future tissue engineering applications.

  @article{Yamashita201685, abstract = {Abstract Despite of the progress made to engineer structured microtissues such as BioMEMS and 3D bioprinting, little control exists how microtissues transform as they mature, as the misbalance between cell-generated forces and the strength of cell-cell and cell-substrate contacts can result in unintended tissue deformations and ruptures. To develop a quantitative perspective on how cellular contractility, scaffold curvature and cell-substrate adhesion control such rupture processes, human aortic smooth muscle cells were grown on glass substrates with submillimeter semichannels. We quantified cell sheet detachment from 3D confocal image stacks as a function of channel curvature and cell sheet tension by adding different amounts of Blebbistatin and TGF-β to inhibit or enhance cell contractility, respectively. We found that both higher curvature and higher contractility increased the detachment probability. Variations of the adhesive strength of the protein coating on the substrate revealed that the rupture plane was localized along the substrate-extracellular matrix interface for non-covalently adsorbed adhesion proteins, while the collagen-integrin interface ruptured when collagen I was covalently crosslinked to the substrate. Finally, a simple mechanical model is introduced that quantitatively explains how the tuning of substrate curvature, cell sheet contractility and adhesive strength can be used as tunable parameters as summarized in a first semi-quantitative phase diagram. These parameters can thus be exploited to either inhibit or purposefully induce a collective detachment of sheet-like microtissues for the use in tissue engineering and regenerative therapies. Statement of Significance Despite of the significant progress in 3D tissue fabrication technologies at the microscale, there is still no quantitative model that can predict if cells seeded on a 3D structure maintain the imposed geometry while they form a continuous microtissue. Especially, detachment or loss of shape control of growing tissue is a major concern when designing 3D-structured scaffolds. Utilizing semi-cylindrical channels and vascular smooth muscle cells, we characterized how geometrical and mechanical parameters such as curvature of the substrate, cellular contractility, or protein-substrate adhesion strength tune the catastrophic detachment of microtissue. Observed results were rationalized by a theoretical model. The phase diagram showing how unintended tissue detachment progresses would help in designing of mechanically-balanced 3D scaffolds in future tissue engineering applications.}, author = {Yamashita, Tadahiro and Kollmannsberger, Philip and Mawatari, Kazuma and Kitamori, Takehiko and Vogel, Viola}, journal = {Acta Biomaterialia}, keywords = {Microstructure}, pages = {85 - 97}, title = {Cell sheet mechanics: How geometrical constraints induce the detachment of cell sheets from concave surfaces}, volume = 45, year = 2016 }
• Avalos Vizcarra, I., Hosseini, V., Kollmannsberger, P., Meier, S., Weber, S.S., Arnoldini, M., Ackermann, M., Vogel, V.: How type 1 fimbriae help Escherichia coli to evade extracellular antibiotics. Scientific Reports. 6, 18109 (2016).
  • [ BibTeX ]
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  @article{avalosvizcarra2016fimbriae, author = {Avalos Vizcarra, Ima and Hosseini, Vahid and Kollmannsberger, Philip and Meier, Stefanie and Weber, Stefan S. and Arnoldini, Markus and Ackermann, Martin and Vogel, Viola}, journal = {Scientific Reports}, keywords = {myown}, month = {jan}, pages = 18109, publisher = {The Author(s)}, title = {How type 1 fimbriae help Escherichia coli to evade extracellular antibiotics}, volume = 6, year = 2016 }

• Foolen, J., Yamashita, T., Kollmannsberger, P.: Shaping tissues by balancing active forces and geometric constraints. Journal of Physics D: Applied Physics. 49, 053001 (2015).
  • [ BibTeX ]
  @article{foolen2015shaping, author = {Foolen, Jasper and Yamashita, Tadahiro and Kollmannsberger, Philip}, journal = {Journal of Physics D: Applied Physics}, keywords = {myown}, number = 5, pages = {053001}, publisher = {IOP Publishing}, title = {Shaping tissues by balancing active forces and geometric constraints}, volume = 49, year = 2015 }

• Hosseini, V., Kollmannsberger, P., Ahadian, S., Ostrovidov, S., Kaji, H., Vogel, V., Khademhosseini, A.: Fiber-Assisted Molding (FAM) of Surfaces with Tunable Curvature to Guide Cell Alignment and Complex Tissue Architecture. Small. 10, 4851–4857 (2014).
  • [ BibTeX ]
  @article{hosseini2014fiber, author = {Hosseini, Vahid and Kollmannsberger, Philip and Ahadian, Samad and Ostrovidov, Serge and Kaji, Hirokazu and Vogel, Viola and Khademhosseini, Ali}, journal = {Small}, keywords = {imported}, number = 23, pages = {4851–4857}, title = {Fiber-Assisted Molding (FAM) of Surfaces with Tunable Curvature to Guide Cell Alignment and Complex Tissue Architecture}, volume = 10, year = 2014 }

• Yamashita, T., Kollmannsberger, P., Mawatari, K., Vogel, V., Kitamori, T.: Curvature-induced spontaneous detachment of vascular smooth muscle cell sheets: towards vascular self assembly in microchannels. Microsystem Technology in Chemistry and Life Science. (2013).
  • [ BibTeX ]
  @article{yamashita2013curvature, author = {Yamashita, T and Kollmannsberger, P and Mawatari, K and Vogel, V and Kitamori, T}, journal = {Microsystem Technology in Chemistry and Life Science}, keywords = {imported}, title = {Curvature-induced spontaneous detachment of vascular smooth muscle cell sheets: towards vascular self assembly in microchannels}, year = 2013 }
• M{\"o}ller, J., Emge, P., Vizcarra, I.A., Kollmannsberger, P., Vogel, V.: Bacterial filamentation accelerates colonization of adhesive spots embedded in biopassive surfaces. New Journal of Physics. 15, 125016 (2013).
  • [ BibTeX ]
  @article{moller2013bacterial, author = {M{\"o}ller, Jens and Emge, Philippe and Vizcarra, Ima Avalos and Kollmannsberger, Philip and Vogel, Viola}, journal = {New Journal of Physics}, keywords = {imported}, number = 12, pages = 125016, publisher = {IOP Publishing}, title = {Bacterial filamentation accelerates colonization of adhesive spots embedded in biopassive surfaces}, volume = 15, year = 2013 }
• Kerschnitzki, M., Kollmannsberger, P., Burghammer, M., Duda, G.N., Weinkamer, R., Wagermaier, W., Fratzl, P.: Architecture of the osteocyte network correlates with bone material quality. Journal of Bone and Mineral Research. 28, 1837–1845 (2013).
  • [ BibTeX ]
  @article{kerschnitzki2013architecture, author = {Kerschnitzki, Michael and Kollmannsberger, Philip and Burghammer, Manfred and Duda, Georg N and Weinkamer, Richard and Wagermaier, Wolfgang and Fratzl, Peter}, journal = {Journal of Bone and Mineral Research}, keywords = {imported}, number = 8, pages = {1837–1845}, publisher = {Wiley Online Library}, title = {Architecture of the osteocyte network correlates with bone material quality}, volume = 28, year = 2013 }
• Bidan, C.M., Kommareddy, K.P., Rumpler, M., Kollmannsberger, P., Fratzl, P., Dunlop, J.W.: Geometry as a factor for tissue growth: towards shape optimization of tissue engineering scaffolds. Advanced healthcare materials. 2, 186–194 (2013).
  • [ BibTeX ]
  @article{bidan2013geometry, author = {Bidan, C{\'e}cile M and Kommareddy, Krishna P and Rumpler, Monika and Kollmannsberger, Philip and Fratzl, Peter and Dunlop, John WC}, journal = {Advanced healthcare materials}, keywords = {imported}, number = 1, pages = {186–194}, publisher = {Wiley Online Library}, title = {Geometry as a factor for tissue growth: towards shape optimization of tissue engineering scaffolds}, volume = 2, year = 2013 }
• Lukas, C., Ruffoni, D., Lambers, F.M., Schulte, F.A., Kuhn, G., Kollmannsberger, P., Weinkamer, R., M{\"u}ller, R.: Mineralization kinetics in murine trabecular bone quantified by time-lapsed in vivo micro-computed tomography. Bone. 56, 55–60 (2013).
  • [ BibTeX ]
  @article{lukas2013mineralization, author = {Lukas, Carolin and Ruffoni, Davide and Lambers, Floor M and Schulte, Friederike A and Kuhn, Gisela and Kollmannsberger, Philip and Weinkamer, Richard and M{\"u}ller, Ralph}, journal = {Bone}, keywords = {imported}, number = 1, pages = {55–60}, publisher = {Elsevier}, title = {Mineralization kinetics in murine trabecular bone quantified by time-lapsed <i>in vivo</i> micro-computed tomography}, volume = 56, year = 2013 }

• Bidan, C.M., Kommareddy, K.P., Rumpler, M., Kollmannsberger, P., Br{\’e}chet, Y.J., Fratzl, P., Dunlop, J.W.: How Linear Tension Converts to Curvature: Geometric Control of Bone Tissue Growth. PloS one. 7, e36336 (2012).
  • [ BibTeX ]
  @article{bidan2012linear, author = {Bidan, C{\'e}cile M and Kommareddy, Krishna P and Rumpler, Monika and Kollmannsberger, Philip and Br{\'e}chet, Yves JM and Fratzl, Peter and Dunlop, John WC}, journal = {PloS one}, keywords = {imported}, number = 5, pages = {e36336}, publisher = {Public Library of Science}, title = {How Linear Tension Converts to Curvature: Geometric Control of Bone Tissue Growth}, volume = 7, year = 2012 }

• Lukas, C., Kollmannsberger, P., Ruffoni, D., Roschger, P., Fratzl, P., Weinkamer, R.: The Heterogeneous Mineral Content of Bone—Using Stochastic Arguments and Simulations to Overcome Experimental Limitations. Journal of Statistical Physics. 144, 316–331 (2011).
  • [ BibTeX ]
  @article{lukas2011heterogeneous, author = {Lukas, C and Kollmannsberger, P and Ruffoni, D and Roschger, P and Fratzl, P and Weinkamer, R}, journal = {Journal of Statistical Physics}, keywords = {imported}, number = 2, pages = {316–331}, publisher = {Springer}, title = {The Heterogeneous Mineral Content of Bone—Using Stochastic Arguments and Simulations to Overcome Experimental Limitations}, volume = 144, year = 2011 }
• Kollmannsberger, P., Bidan, C., Dunlop, J., Fratzl, P.: The physics of tissue patterning and extracellular matrix organisation: how cells join forces. Soft Matter. 7, 9549–9560 (2011).
  • [ BibTeX ]
  @article{kollmannsberger2011physics, author = {Kollmannsberger, P and Bidan, CM and Dunlop, JWC and Fratzl, P}, journal = {Soft Matter}, keywords = {imported}, number = 20, pages = {9549–9560}, publisher = {Royal Society of Chemistry}, title = {The physics of tissue patterning and extracellular matrix organisation: how cells join forces}, volume = 7, year = 2011 }
• Kollmannsberger, P., Mierke, C.T., Fabry, B.: Nonlinear viscoelasticity of adherent cells is controlled by cytoskeletal tension. Soft Matter. 7, 3127–3132 (2011).
  • [ BibTeX ]
  @article{kollmannsberger2011nonlinear, author = {Kollmannsberger, Philip and Mierke, Claudia Tanja and Fabry, Ben}, journal = {Soft Matter}, keywords = {imported}, number = 7, pages = {3127–3132}, publisher = {Royal Society of Chemistry}, title = {Nonlinear viscoelasticity of adherent cells is controlled by cytoskeletal tension}, volume = 7, year = 2011 }
• Kollmannsberger, P., Fabry, B.: Linear and nonlinear rheology of living cells. Annual Review of Materials Research. 41, 75–97 (2011).
  • [ BibTeX ]
  @article{kollmannsberger2011linear, author = {Kollmannsberger, Philip and Fabry, Ben}, journal = {Annual Review of Materials Research}, keywords = {myown}, pages = {75–97}, publisher = {Annual Reviews}, title = {Linear and nonlinear rheology of living cells}, volume = 41, year = 2011 }

• Mierke, C.T., Kollmannsberger, P., Zitterbart, D.P., Diez, G., Koch, T.M., Marg, S., Ziegler, W.H., Goldmann, W.H., Fabry, B.: Vinculin facilitates cell invasion into three-dimensional collagen matrices. Journal of Biological Chemistry. 285, 13121–13130 (2010).
  • [ BibTeX ]
  @article{mierke2010vinculin, author = {Mierke, Claudia T and Kollmannsberger, Philip and Zitterbart, Daniel Paranhos and Diez, Gerold and Koch, Thorsten M and Marg, Susanna and Ziegler, Wolfgang H and Goldmann, Wolfgang H and Fabry, Ben}, journal = {Journal of Biological Chemistry}, keywords = {imported}, number = 17, pages = {13121–13130}, publisher = {ASBMB}, title = {Vinculin facilitates cell invasion into three-dimensional collagen matrices}, volume = 285, year = 2010 }

• Kollmannsberger, P., Fabry, B.: Active soft glassy rheology of adherent cells. Soft Matter. 5, 1771–1774 (2009).
  • [ BibTeX ]
  @article{kollmannsberger2009active, author = {Kollmannsberger, Philip and Fabry, Ben}, journal = {Soft Matter}, keywords = {imported}, number = 9, pages = {1771–1774}, publisher = {The Royal Society of Chemistry}, title = {Active soft glassy rheology of adherent cells}, volume = 5, year = 2009 }
• Diez, G., Kollmannsberger, P., Mierke, C.T., Koch, T.M., Vali, H., Fabry, B., Goldmann, W.H.: Anchorage of vinculin to lipid membranes influences cell mechanical properties. Biophysical journal. 97, 3105–3112 (2009).
  • [ BibTeX ]
  @article{diez2009anchorage, author = {Diez, Gerold and Kollmannsberger, Philip and Mierke, Claudia T and Koch, Thorsten M and Vali, Hojatollah and Fabry, Ben and Goldmann, Wolfgang H}, journal = {Biophysical journal}, keywords = {imported}, number = 12, pages = {3105–3112}, publisher = {Elsevier}, title = {Anchorage of vinculin to lipid membranes influences cell mechanical properties}, volume = 97, year = 2009 }
• Kasza, K., Nakamura, F., Hu, S., Kollmannsberger, P., Bonakdar, N., Fabry, B., Stossel, T., Wang, N., Weitz, D.: Filamin A is essential for active cell stiffening but not passive stiffening under external force. Biophysical journal. 96, 4326–4335 (2009).
  • [ BibTeX ]
  @article{kasza2009filamin, author = {Kasza, KE and Nakamura, F and Hu, S and Kollmannsberger, P and Bonakdar, N and Fabry, B and Stossel, TP and Wang, N and Weitz, DA}, journal = {Biophysical journal}, keywords = {imported}, number = 10, pages = {4326–4335}, publisher = {Elsevier}, title = {Filamin A is essential for active cell stiffening but not passive stiffening under external force}, volume = 96, year = 2009 }
• Lorenz, C., Brunner, J.G., Kollmannsberger, P., Jaafar, L., Fabry, B., Virtanen, S.: Effect of surface pre-treatments on biocompatibility of magnesium. Acta biomaterialia. 5, 2783–2789 (2009).
  • [ BibTeX ]
  @article{lorenz2009effect, author = {Lorenz, Carla and Brunner, Johannes G and Kollmannsberger, Philip and Jaafar, Leila and Fabry, Ben and Virtanen, Sannakaisa}, journal = {Acta biomaterialia}, keywords = {imported}, number = 7, pages = {2783–2789}, publisher = {Elsevier}, title = {Effect of surface pre-treatments on biocompatibility of magnesium}, volume = 5, year = 2009 }

• Mierke, C.T., Zitterbart, D.P., Kollmannsberger, P., Raupach, C., Schl{\"o}tzer-Schrehardt, U., Goecke, T.W., Behrens, J., Fabry, B.: Breakdown of the endothelial barrier function in tumor cell transmigration. Biophysical journal. 94, 2832–2846 (2008).
  • [ BibTeX ]
  @article{mierke2008breakdown, author = {Mierke, Claudia Tanja and Zitterbart, Daniel Paranhos and Kollmannsberger, Philip and Raupach, Carina and Schl{\"o}tzer-Schrehardt, Ursula and Goecke, Tamme Weyert and Behrens, J{\"u}rgen and Fabry, Ben}, journal = {Biophysical journal}, keywords = {imported}, number = 7, pages = {2832–2846}, publisher = {Elsevier}, title = {Breakdown of the endothelial barrier function in tumor cell transmigration}, volume = 94, year = 2008 }
• R{\"o}sel, D., Br{\’a}bek, J., Tolde, O., Mierke, C.T., Zitterbart, D.P., Raupach, C., Bicanov{\’a}, K., Kollmannsberger, P., Pa{\v{n}}kov{\’a}, D., Vesel{\`y}, P., others: Up-regulation of Rho/ROCK signaling in sarcoma cells drives invasion and increased generation of protrusive forces. Molecular Cancer Research. 6, 1410–1420 (2008).
  • [ BibTeX ]
  @article{rosel2008up, author = {R{\"o}sel, Daniel and Br{\'a}bek, Jan and Tolde, Ond{\v{r}}ej and Mierke, Claudia T and Zitterbart, Daniel P and Raupach, Carina and Bicanov{\'a}, Krist{\`y}na and Kollmannsberger, Philip and Pa{\v{n}}kov{\'a}, Daniela and Vesel{\`y}, Pavel and others}, journal = {Molecular Cancer Research}, keywords = {imported}, number = 9, pages = {1410–1420}, publisher = {AACR}, title = {Up-regulation of Rho/ROCK signaling in sarcoma cells drives invasion and increased generation of protrusive forces}, volume = 6, year = 2008 }
• Mierke, C.T., Kollmannsberger, P., Paranhos Zitterbart, D., Smith, J., Fabry, B., Goldmann, W.H.: Mechano-coupling and regulation of contractility by the vinculin tail domain. Biophysical journal. 94, 661–670 (2008).
  • [ BibTeX ]
  @article{mierke2008mechano, author = {Mierke, Claudia Tanja and Kollmannsberger, Philip and Paranhos Zitterbart, Daniel and Smith, James and Fabry, Ben and Goldmann, Wolfgang Heinrich}, journal = {Biophysical journal}, keywords = {imported}, number = 2, pages = {661–670}, publisher = {Elsevier}, title = {Mechano-coupling and regulation of contractility by the vinculin tail domain}, volume = 94, year = 2008 }

• Kollmannsberger, P., Fabry, B.: High-force magnetic tweezers with force feedback for biological applications. Review of Scientific Instruments. 78, 114301–114301 (2007).
  • [ BibTeX ]
  @article{kollmannsberger2007high, author = {Kollmannsberger, Philip and Fabry, Ben}, journal = {Review of Scientific Instruments}, keywords = {imported}, number = 11, pages = {114301–114301}, publisher = {AIP}, title = {High-force magnetic tweezers with force feedback for biological applications}, volume = 78, year = 2007 }