Leibniz Cooperative Excellence

EpiC4TT: Epigenetic control of thymic CD4+ T lymphocyte development in humans – paving the way for new iPSC-derived T cell therapies

T lymphocytes play a crucial role in the adaptive immune system by targeting pathogens and tumor cells. They are used in personalized adoptive cell therapies for leukemia treatment, but their full potential for other diseases, especially CD4+ T cell populations for the treatment of autoimmune diseases, has not been fully exploited.
The project aims to understand the epigenetic mechanisms involved in CD4+ T cell maturation and replicate them in hiPSC-based differentiation systems. By comparing DNA methylation patterns in thymocytes from human donors, humanized mice, and hiPSC-derived cell cultures, the project seeks to identify critical epigenetic regulators for human T cell development. Using CRISPR-Cas9 technology and mouse models, the researchers aim to improve hiPSC-based T cell generation protocols and enhance therapeutic T cell products.

Cooperating partners

German Rheumatism Research Centre Berlin (DRFZ)

Julia Polansky (Coordinator)

Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)

Claudia Waskow

Berlin Institute of Health @Charité

Harald Stachelscheid

Tick Tock: Linking Pathology and Lifestyle to Epigenetic Determinants of Biological vs. Chronological Stem Cell Aging

Aging leaves traces in our DNA. These traces, co-called DNA methylations, can be read by researchers to accurately determine an organism’s age. However, the determination of an organism’s age alone is not a proof that methylation itself directly affects the process of aging.

Causal relationships

This project aims to find exactly these causal connections between DNA methylation and aging. The researchers focus on hematopoietic stem cells, which give rise to immune cells. Immune cells are a particular example of cells that lose their functions in aging organisms. Therefore, the project will contribute significantly to our understanding of aging processes and to the development of therapeutic interventions.

Cooperating partners

Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)

Björn von Eyss(Coordinator)
Steve Hoffmann

German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE)

Tim Schulz

Hannover Medical School (MHH)

Florian Heidel

XpandHSC: Ex vivo Expansion of Functional Human Hematopoietic Stem Cells to Improve Therapy

One important limiting factor for successful clinical therapies using hematopoietic stem cells (HSCs) is the low number of histocompatible donor cells available for a specific patient. This caveat is based on the lack of understanding and, correspondingly, the lack of available protocols for the cultivation or even expansion of functional human HSCs in vitro.

Interdisciplinary approach

Our goal is to understand mechanisms of the regulation of HSCs and to use this understanding to expand human HSCs in vitro using advanced culture systems. In these culture systems we model the three-dimensional stem cell niche using molecular factors mediating the expansion of HSCs while preserving their functionality in vitro. Successful expansion of human HSCs is validated using innovative mouse models supporting human HSC engraftment in vivo.

Combined expertise

To meet this challenge we assembled a team that combines expertise in fundamental hematopoietic stem cell research (Waskow Lab), proteomics (Ori Lab) and clinical application (Heidel Lab) with expert bioinformatic analysis (Höfer Lab), and material scientists (Werner Lab). This collaboration involves the bioinformatic integration of gene expression and proteome data of HSCs and defined niche cells from their immediate microenvironment in vivo and will lead to the identification of novel regulatory candidate genes.

Development of improved therapies

The candidates will be used in innovative 3D culture systems based on tailored biohybrid hydrogels, a modular matrix platform based on glycosaminoglycans, and tested for their suitability for the cultivation of human HSCs. Validation of the most effective culture conditions that support the maintenance and expansion of human HSCs will be performed by transplantation experiments into excellent recipient mouse models generated within the consortium.

Taken together, our interdisciplinary approach will provide detailed information on the influence of extracellular matrix, cytokines, the mechanical properties of the cellular environment such as stiffness, and the effects of specific molecular regulators on the maintenance and expansion of HSCs in vitro, hopefully contributing to the development of improved clinical therapies.

Cooperating partners

Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)