Pluripotent Profiles

Robert Zweigerdt
Robert Zweigerdt
Principal Investigator, Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School (MHH)

Dr. Zweigerdt completed his PhD in Germany under the supervision of Hans-Henning Arnold and Thomas Braun, studying early skeletal muscle development and transcriptional gene regulation in transgenic mice and embryonic stem cells. Following his PhD, Dr. Zweigerdt moved to Cardion AG and was instrumental in developing a novel process for the large scale production of pure, ESC-derived cardiomyocytes in collaboration with Jürgen Lehman and Loren Field.

At ES Cell International, Dr. Zweigerdt was responsible for a program aiming at the clinical translation of human ESC-derived cardiomyocytes and was involved in the characterization of the world's first clinical-grade human ESC lines. In 2007 he was appointed Principal Investigator (PI) at the A*Star Institute of Medical Biology in Singapore. He is now a PI at the Leibniz Research Laboratories for Biotechnology and Artificial Organs at Hannover Medical School, part of the Excellence Cluster "REBIRTH", working on clinical scale and grade production of hiPSCs and using hiPSC-derived cardiomyocytes in pre-clinical animal models of heart failure.

1. What is your academic background?
I was fascinated by cellular and molecular biology from early on. The possibility to manipulate cells and their genome and to subsequently follow their fate in vitro and in animal models is still extremely fascinating to me. My PhD thesis was dedicated to early steps controlling skeletal muscle development in mammals, using transgenic mice as a model. This is when I have also started to culture, engineer, and differentiate mouse embryonic stem cells.

Thereafter, working as a scientist in biotech companies, I developed strategies on how pluripotent stem cells can be cultured and differentiated in relevant numbers and quality to enable their therapeutic application.

2. Who is your scientific idol?
Thomas Braun, who is now Director of the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, spurred my scientific interest by introducing me to gene targeting in mouse embryonic stem cells, including all practical steps involved in generating and analyzing respective mouse models. This was in the early 1990s, when the technology was still quite new. Capecchi, Evans and Smithies didn’t receive the Nobel Prize for it until 2007.

Later, the comprehensive and critical work of Loren Field (Indianapolis, US) and Christine Mummery (Leiden, Netherlands) on the cardiomyogenic differentiation of pluripotent stem cells and their application for heart repair were most influential to me.

3. What’s the focus of your current work?
My key focus is on translating human pluripotent stem cell culture and their cardiomyogenic differentiation into robust, well controlled and clinical relevant processes for cardiomyocyte production.

But as a member of the REBIRTH cluster of excellence here in Hannover, application of the technology to other lineages such as endothelial cells, respiratory epithelial cells, hepatocytes, and blood cells is ongoing in close collaboration with colleagues, who are experts for the regeneration of respective organs.

Finally, monitoring transplanted cells by innovative imaging technology in physiologically relevant disease models, such as myocardial infarction in pigs, is an important goal.

On PSC Research

1. What do you consider to be the most important advance(s) in stem cell research over the past 5 years?
Besides the progress in hiPSC technology, small molecule-based improvement of cell culture and differentiation is a key progress. It enables better control of culture and differentiation processes and is also more compatible with the idea of GMP-compliant mass production of cells for clinical applications.

2. What advances do you hope the field will achieve in the next 5 years?
I envision the routine application of hPSC-derived lineages for in vitro disease modeling in pharmacology research, tissue engineering, and a better understanding of in vitro lineage maturation.

3. There have recently been a number of interesting papers on transdifferentiation. What impact do you see this technology having on the pluripotent field?
This will likely result in ground breaking options for novel treatments in the long run. However, at present, initial "effects" have been described lacking an understanding of the underlying mechanisms. Another issue is the currently low efficiency of the technology, which will require magnitudes of improvement. Reprogramming to a pluripotent state in vitro, even if the efficiency is low, allows for the "unlimited" expansion of an initial colony.

In contrast, transdifferentiation into a functional cell type, such as cardiomyocytes, usually results in the formation of cells with a low proliferation potential, requiring high efficiency of the process to generate adequate numbers of target cells. However, improvement by small molecule effectors might result in great progress.

4. Some recent studies have suggested important differences between iPS cells and ES cells, particularly in terms of their epigenetic marks. How similar do you see iPS cells and ES cells being, and what is your view of the potential of iPS cells for cell therapy and disease modeling?
I don't think that some degree of epigenetic variability will be a major issue for disease modeling, as long as respective controls are included. Ideally, an iPS line's specific disease phenotype should be rescued by homologous recombination-based repair to prove that a particular disease-related mutation is responsible for the observed phenotype. But genomic abnormalities – which seem to be induced or enriched in the process of reprogramming or during long term culture – possess high safety issues for envisioned therapeutic applications.

5. What are the main technical challenges facing the pluripotent field currently?
Technical hurdles of hPSC culture will be mainly resolved in the near future, given the recent progress in the field. Further in vitro maturation of hPSC-derived lineages and formation of functional, vascularized 3D tissue will remain a technical issue, as well as the formidable challenge of the functional integration of transplanted cells and tissues for in vivo organ repair.

On mTeSR™1

1. How long have you been using mTeSR™1 ?
We have been using mTeSR™1 for more than 5 years. By direct comparison to alternative media, we found that this was the only product supporting long-term, multi passage suspension culture of numerous human pluripotent cell lines.

It has absolutely enabled our research; it was the first medium formulation that enabled single cell inoculated suspension culture of human pluripotent stem cells as cell-only-aggregates and is still our "gold standard" for this culture format, which is in the centre of our work. Importantly, hPSC expansion in mTeSR™1 is compatible with our subsequent differentiation protocols into functional cell types such as cardiomyocytes.

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