Human iPSC Models and Organoids

The Fraunhofer ITMP stem cell team generates and subsequently characterizes human induced pluripotent stem cells (hiPSC) from both healthy donors and patients. Robust differentiation protocols for various cell types ((neuro)ectodermal, mesodermal and endodermal) are used for the differentiation of these cells, whereby both 2D and 3D formats (including organoids) are in use.

Another important aspect of our work is the multiparametric cellular phenotyping of hiPSC-based disease models enabled by high content imaging. In addition, the work includes the development and adaptation of assays and process automation to increase their efficiency and throughput.

The assessment of the efficacy and toxicity of small molecule drug candidates also plays a central role. In this context, permeation studies are carried out using in-vitro blood-brain barrier models to analyze the permeability of potentially active substances.

Core Expertise:

Use of established iPSC lines from large national and international iPSC repositories
Robust differentiation of human iPSCs into disease-relevant cell types and tissues of (neuro)ectodermal, mesodermal, and endodermal origin in 2D and 3D formats
Continuous development, optimization, and process automation of cell-based assays
Functional characterization of complex iPSC-based models, including brain organoids and engineered cardiac muscle tissues

Objectives/Services:

Customized generation and quality control of human iPSCs from patient samples and healthy donors
Genome editing in iPSCs to generate isogenic control and disease models as well as iPSC reporter cell lines
Multiparametric molecular and cellular phenotyping of iPSC disease models including optimization for high-content imaging
Evaluation of the efficacy and toxicity of small molecule drug candidates
Permeability studies with in-vitro blood-brain barrier models

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Selected Projects

BioDEL

The aim of the BioDEL project is to develop human in-vitro test systems for standardised and predictive high-throughput testing of PROTACs and other molecular degraders, and to establish carrier platform technologies that will allow the rational development of a customised carrier system for the targeted delivery of a specific PROTAC molecule. In addition, predictive in-vitro to in-vivo correlations (IV-IC) and in-silico models will be developed to enable future successful therapeutic use of PROTACs.

CureMILS/SynLeigh

Mitochondrial DNA (mtDNA)-associated Leigh syndrome (MILS) is an untreatable rare brain disease in infants and children. MILS is typically caused by mtDNA mutations in the ATP-generating subunit MT-ATP6. This consortium has employed neural cells generated from MILS patients via cellular reprogramming to carry out large-scale screenings using repurposable drugs, thereby allowing the identification of new therapeutic strategies. We identified phosphodiesterase 5 inhibitors (PDE5i) as a potential therapeutic option for MILS and confirmed its positive effect in extensive multi-omic studies. Compassionate use of PDE5i was shown to be beneficial in MILS patients. A multi-national clinical trial and a concrete path towards a new standard of care for MILS has been initiated.

COMMUTE

COMMUTE aims at systematically collecting evidence for the co-morbidity between COVID-19 and neurodegenerative diseases (such as Alzheimer’s and Parkinsonism). One key goal of COMMUTE is to unravel the mechanisms underlying the possible link between SARS-CoV-2 and neurodegeneration and to generate models that allow for personalized risk assessment for COVID-19-induced cognitive decline. The other major goal of COMMUTE is to develop cellular assay systems that identify drug-repurposing candidates that prevent or reduce COVID-19-induced risk for neurodegeneration. Finally, the ethical and legal work in the consortium will come up with recommendations for handling ethical and legal aspects of virus-induced neurodegenerative disease risk.

Weiterführende Informationen

CELLebrate

Aim of the CELLebrate project is the establishment of an innovative live-cell-painting platform for parallel analysis of various subcellular structures in real time. Through stable integration of fluorescent markers into different organelles of hiPSCs via gene editing, changes in morphology and organization of cellular components can be dynamically traced. This enables the investigation of the effects and toxicity of potential drugs in disease-relevant cell types, such as cardiomyocytes or neurons, in patient-relevant in vitro models. The project aims to improve preclinical drug testing and thereby to contribute to the development of safer and more effective therapies.

MEK2

Cardio-facio-cutaneous (CFC) syndrome is a rare genetic developmental disorder presented with neurological abnormalities, among other symptoms. Despite severe neurological defects being particularly associated with mutations in the MEK2 gene, the effects of MEK2 dysfunction on brain development remain poorly understood. The aim of this project is to investigate the effects of MEK2 mutations on brain development and function using patient-specific hiPSCs and corresponding isogenic control lines. By differentiating these cells into relevant cell types of the central nervous system, including neurons, astrocytes, and microglia, disease-relevant changes at molecular and functional level will be analyzed in 2D and 3D in vitro models. The ultimate goal is to improve the understanding of the underlying molecular disease mechanisms to advance the development of new therapeutic strategies for CFC syndrome.

Selected Publications

Fell J, Pavez-Giani MG, Koitka F, Kensah G, Santos GL, van der Vorst EPC, Lenz C, Salinas G, Busley AV, Fedorenko A, Hindmarsh R, Wolf CM, Lutz S, Hasenfuss G, Zimmermann WH, Wollnik B, Cyganek L. Targeting Interleukin-8-Mediated Cellular Crosstalk Reverses Hypertrophic Cardiomyopathy and Cardiac Fibrosis in Noonan Syndrome.
Circulation. 2026.
doi: 10.1161/CIRCULATIONAHA.125.074155

Zink A*, Dai D*, Wittich A*, Henke MT*, Pedrotti G*, Heiduschka S*, … Brunetti D*, Del Sol A*, Bottani E*, Pless O*, Schuelke M*, Prigione A*.
Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy.
Cell 2026 Mar 19;44(1):1591-1874.
doi: 10.1016/j.cell.2026.02.008

Krieg K, Materna-Reichelt S, Naber T, Rachad FZ, Kauven P, Weller A, Haferkamp U, Wittich A, Zaliani A, Woo MS, Walkenhorst M, Siegmund M, Harberts J, Zierold R, Blick R, Conze C, Muschong P, Miltner D, Friese MA, Mezler M, Siegmund H, Evert K, Krasemann S, Gužvić NS, Klein CA, Werner-Klein M, Wegener J, Pless O. Cortical organoid-derived models of the melanoma brain metastatic niche enable prioritization of cancer-targeting drugs.
Cell Reports Methods 2025 Dec 15;5(12):101236.
doi: 10.1016/j.crmeth.2025.101236

Busley AV, Gutiérrez-Gutiérrez Ó, Hammer E, Koitka F, Mirzaiebadizi A, Steinegger M, Pape C, Böhmer L, Schroeder H, Kleinsorge M, Engler M, Cirstea IC, Gremer L, Willbold D, Altmüller J, Marbach F, Hasenfuss G, Zimmermann WH, Ahmadian MR, Wollnik B, Cyganek L. Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.
Cell Reports. 2024; 43(7):114448.
doi: 10.1016/j.celrep.2024.114448

Knauer C, Haltern H, Schoger E, Kügler S, Roos L, Zelarayán LC, Hasenfuss G, Zimmermann WH, Wollnik B, Cyganek L. Preclinical evaluation of CRISPR-based therapies for Noonan syndrome caused by deep-intronic LZTR1 variants.
Mol Ther Nucleic Acids. 2024; 35(1):102123.
doi: 10.1016/j.omtn.2024.102123