24 June 2021

Hubrecht researchers receive funding from ZonMw for three collaborative projects using stem cell-based models

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The “Pluripotent Stem cells for Inherited Diseases and Embryonic Research (PSIDER)” programme of the ZonMw supports projects using induced pluripotent stem cells (iPS cells) for biomedical research. These iPS cells can give rise to any type of cell in the body and therefore hold great promise for regenerative medicine. Three independent consortia, in which Hubrecht researchers participate, now receive funding from this programme. The group of Eva van Rooij will use iPS cells to develop gene editing therapies in an attempt to cure cardiomyopathies – diseases of the heart muscle. The groups of Jop Kind and Ina Sonnen will develop and study blastoids as a model system of early embryonic development. The group of Alexander van Oudenaarden will develop a human gastruloid model from iPS cells.

Using iPS cell technology to develop prime editing therapies for heart disease

Inherited cardiomyopathies are a group of disorders of the heart muscle. They are caused by mutations in key genes that lead to a variety of severe disorders. Current treatments focus on symptom relieve and no cure is currently available. Prime editing is a breakthrough gene editing technology. This recent discovery allows gene editing with less restrictions and greater precision than CRISPR-Cas9 – the current leading gene editing technology. Prime editing provides an exciting opportunity to develop new therapies for inherited cardiomyopathies.

The project of the group of Eva van Rooij will use prime editing to further develop a cure for the most pathogenic inherited cardiomyopathies. Patient-derived induced pluripotent stem cells (hiPSCs) can be used to develop these prime editing tools. hiPSCs are cells that can give rise to any type of cell in the body. “We will optimize the tools using cutting-edge 3D cardiac tissues such as organoids generated from hiPSCs. Our research will be heavily embedded within society and in continuous communication with stakeholders including the general public,” says van Rooij.

Picture of Eva Van Rooij

 

 

Eva van Rooij is group leader at the Hubrecht Institute and professor of Molecular Cardiology at the University Medical Center Utrecht.

Beyond the blastocyst: modeling human embryology with stem cells

When mistakes occur during cell division, cells can end up with an unequal number of chromosomes. This is called chromosomal aneuploidy. Chromosomal aneuploidies are frequently found in human IVF embryos and are a main cause of pregnancy loss. Progress in the study of human development and the impact of aneuploidies is slow due to the limited number of embryos available for research and experimental and ethical constraints. Jop Kind and Ina Sonnen in collaboration with researchers from the Erasmus MC, Radboud University and IMBA Vienna, will analyze the mechanisms of human development at an unprecedented level of cellular and molecular detail using so-called human blastoids. These blastoids model embryos of approximately 5 days after fertilization – the blastocyst-stage – and are generated entirely from stem cells.

The researchers will combine cutting-edge technologies to construct a 4D map of human development and dissect the cellular interactions that guide early decisions about the type of cell that is formed and how it will be shaped. They will then investigate how chromosomal aberrations affect these developmental mechanisms and explore interventions that promote healthy development. In complementary research, they will develop an ethical framework for sound policy-making with regards to human embryo model research and its clinical applications.

Image Ina

 

 

Ina Sonnen is group leader at the Hubrecht Institute.

Image Kind

 

 

Jop Kind is group leader at the Hubrecht Institute and Oncode Investigator.

GREAT: 3D gastruloid cultures to model normal and pathogenic human development

Gastrulation is a crucial event in early human development during which the multi-layered organism begins to take form. Proper understanding of this process in humans is essential for predicting and preventing developmental disorders as well as for identifying factors that might affect adult health and longevity. Research on human gastrulation is complicated by a lack of tractable study material. The process occurs before awareness of pregnancy: even at 5-6 weeks of gestation when the very earliest abortion material is available for research, gastrulation is long over. Current Dutch laws on embryo use for research prohibits their culture beyond 14 days and, at that time point, gastrulation has not yet started.

The group of Alexander van Oudenaarden, in collaboration with researchers from the LUMC, UMCU, UMCG and the Erasmus MC, aims to transform the understanding of human development to benefit human health and disease. They will develop an advanced in vitro, 3D human gastruloid model from hiPSCs. Other researchers recently took major steps towards developing human gastruloids with human embryonic stem cells (hESCs), but advanced processes do not yet occur in this system. The project, which is called GREAT and will be led by Niels Geijsen (LUMC), will advance the gastruloid system with hESCs and hiPSCs. They will generate a comprehensive map of early human development, and uncover new causes and solutions to abnormal organ formation resulting from genetic disorders. In parallel, the researchers will assess the ethical issues arising from these embryonic models to ensure that the model that can be used responsibly in research.

Image van Oudenaarden

 

 

Alexander van Oudenaarden is group leader at the Hubrecht Institute, professor of quantitative biology of gene regulation at the University Medical Center Utrecht and Utrecht University, and Oncode Investigator.