Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the cerebellum as their main... Show moreDominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the cerebellum as their main hallmark. Although animal and cell models have been highly instrumental for our current insight into the underlying disease mechanisms of these neurodegenerative disorders, they do not offer the full human genetic and physiological context. The advent of human induced pluripotent stem cells (hiPSCs) and protocols to differentiate these into essentially every cell type allows us to closely model SCAs in a human context. In this review, we systematically summarize recent findings from studies using hiPSC-based modelling of SCAs, and discuss what knowledge has been gained from these studies. We conclude that hiPSC-based models are a powerful tool for modelling SCAs as they contributed to new mechanistic insights and have the potential to serve the development of genetic therapies. However, the use of standardized methods and multiple clones of isogenic lines are essential to increase validity and reproducibility of the insights gained. Show less
Studying diseases or effects of new drugs on the human body is challenging, not least because of the lack of proper testing models that recapitulate human physiology. Most research is done using... Show moreStudying diseases or effects of new drugs on the human body is challenging, not least because of the lack of proper testing models that recapitulate human physiology. Most research is done using animal models but these often show differences with humans in disease manifestation and responses to drugs. For example, drugs that had no effect on the hearts of animals later turned out to cause lethal arrhythmias in some humans. This – and the ethical issues around animal testing – is why, as in this thesis, there is increasing interest on making human heart models based on pluripotent stem cells (hPSCs). Nowadays small numbers of cells can be collected from a patient (e.g. from blood, urine or skin), reprogrammed to hiPSCs, and then differentiated to heart muscle cells (cardiomyocytes). Since the genetics of the patient are maintained during reprogramming, the phenotype of a genetic disease affecting cardiac function can also be captured. The focus of this thesis has been developing methods to measure these cardiac phenotypes robustly and with sufficient complexity to reflects drug responses and disease of the heart. Our results supported the notion that hPSC models will become human avatars and accurate measurement models able to recapitulate essential human-specific processes. Show less
Putten, M. van; Hmeljak, J.; Aartsma-Rus, A.; Dowling, J.J. 2020
Neuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment... Show moreNeuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment exists for any of the NMDs. For multiple disorders, however, therapeutic strategies are currently being tested in clinical settings, and the first successful treatments have now entered clinical practice (e.g. spinraza for spinal muscular atrophy). Successful clinical translation depends on the quality and translatability of preclinical findings and on the predictive value of the experimental models used in their initial development. This Special Issue of Disease Models & Mechanisms has a particular focus on translational research for NMDs. The collection includes original research focusing on advances in the development of novel in vitro and in vivo models, broader understanding of disease pathology and progression, and approaches to modify the disease course in these models. We also present a series of special articles and reviews that highlight our understanding of cellular mechanisms, biomarkers to tract disease pathology, the diversity of mouse models for NMDs, the importance of high-quality preclinical studies and data validation, and the pitfalls of successfully moving a potential therapeutic strategy to the clinic. In this Editorial, we summarize the highlights of these articles and place their findings in the broader context of the NMD research field. Show less
Chen, Z.F.; Xian, W.Y.; Bellin, M.; Dorn, T.; Tian, Q.H.; Goedel, A.; ... ; Sinnecker, D. 2017
The research described in this thesis focuses on the use of both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to understand cardiac lineage development and disease. To... Show moreThe research described in this thesis focuses on the use of both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to understand cardiac lineage development and disease. To investigate the possibility of studying inherited cardiac diseases, we compared pluripotent stem cell-derived cardiomyocytes by investigating both a mouse and human model of a complex cardiac overlap syndrome caused by a mutation in the gene SCN5A. We demonstrated that both ESC- and iPSC-derived cardiomyocytes can recapitulate the characteristics of the disease. Furthermore this thesis describes a detailed protocol to differentiate human pluripotent stem cells to cardiomyocytes that was applied in the study comparing hESC- and hiPSC- derived cardiomyocytes at several time points during cardiac differentiation. We targeted fluorescent marker GFP to one allele of NKX2-5 in a human iPSC line that now matched a similar human ESC reporter line previously generated in the laboratory. This offered the opportunity to obtain cardiomyocytes and their precursors at different time points during the differentiation and determine the true degree of similarity between both pluripotent stem cell sources. Additionally the same hESC- and hiPSC-derived cardiomyocytes were compared to a unique set of foetal heart samples. Show less
