Predictive, Preventive and Personalized Medicine & Molecular Diagnostics

Biography

Biography: J. Hescheler

Abstract

 Due to their ability to reproduce the embryonic, neonatal and adult differentiation of all different organotypic cellular phenotypes, pluripotent stem cells represent an ideal tool to study physiological processes of embryogenesis under in vitro conditions as well as to provide the basis of cellular therapeutics, to build up test assay systems for drug discovery or toxicology and to develop novel disease models for companion diagnostics within personalized medicine. In particular, embryonic (ES) and induced pluripotent stem (iPS) cells can reproduce all organotypic electrophysiology, signalling cascades and genes involved in the development (functional genomics). This occurs spontaneously within three-dimensional cell aggregates – embryoid bodies (EBs) – which I developed 25 years ago. To select only one lineage, e.g. the cardiac lineage, and to allow the identification of the transplanted cells, transgenic ES and iPS cells were used. They contained a vector with two cloning sites for EGFP and a puromycin resistance for selection under the alpha-MHC promoter – a technology which allowed an easy transfer to bioreactor systems for large scale production.

We aimed at generating iPS cell-derived cardiomyocytes (CMs) and their molecular and functional characterization in comparison to CMs derived from established ES cells on a transcriptomic and electrophysiological level. To demonstrate the ability of ES cells for regenerative medicine and tissue repair, cardiomyocytes differentiated from ES cells were injected into the cryoinfarcted left ventricular wall of adult wild-type mice. Translation from the laboratory into the clinic is one of the remaining key issues remaining for applied stem cell research.

Within two European consortia, ESNATS and DETECTIVE, under my coordination a battery of toxicity tests was developed using human ES or human iPS lines subjected to different standardised culture protocols. Tests cover embryoid bodies in different developmental stages including early embryonic stages (embryotoxicity), neuronal lineages (neurotoxicity), complemented with test systems for hepatic metabolism and cardiac development (cardio-toxicity). Predictive toxicogenomics and -proteomics markers were identified allowing a better predicitvity of human test systems, to reduce, refine and replace animal tests, to lower testing costs, and to support medium/high throughput testing which will be of relevance for companion diagnostics and personalized medicine. .

Reprogramming of fibroblasts from patients with poly- or monogenetic diseases including LQT3 or CPVT syndrome resulted in generation of iPS cells for disease modelling. This novel approach may also enable patient-specific cell replacement therapies, which appears

to be an indispensable prerequisite for a later use in clinics. iPS cells from patients represent a new diagnostic tool for precision medicine, for better analysis of the pathophysiology and to develop personalised strategies for an optimized therapy.