Research Siebe Van Calster

Abstract

Stroke has a dramatic, lasting influence on the lives of millions of patients worldwide. Despite decades of research, none of the candidate neuroprotective drugs have made it to an effective therapy to date. This is partially due to the lack of appropriate model systems that recapitulate the human ischemic responses. Fortunately, induced pluripotent stem cell (iPSC)-technology has provided a new entry point for generating relevant human-based in vitro brain models, such as neurospheroids. Capitalizing on the successful research efforts of my host group to generate human iPSC-derived tripartite neurospheroids that contain mature neurons, astrocytes and microglia, we hypothesize that such models will help unravel biologically relevant cellular and molecular events in the context of stroke pathology. To investigate this, we will emulate stroke-like conditions in these model systems by means of oxygen and glucose deprivation and subsequently characterize the functional and molecular changes using a combined imaging and multi-omics approach. Furthermore, we will refine the current tripartite model, by allowing the infiltration of peripheral immune cells (i.e., monocytes and neutrophils) to mimic the in vivo response even more comprehensively. This way, we intend to unravel the neuroinflammatory cascade that follows ischemic stroke and identify new pathways and associated markers that may help protect or repair the neurological damage.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: De Vos Winnok
• Co-promoter: Van Breedam Elise
• Fellow: Van Calster Siebe

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Due to the enormous impact of stroke on the patient's quality of life and on society, decades of research resulted in the identification of thousands of candidate neuroprotective drugs. Unfortunately, none have led to an effective therapy to date. This can partially be attributed to the lack of in vitro systems able to accurately recapitulate human ischemic responses. Fortunately, the advent of induced pluripotent stem cell (iPSC)-technology has provided novel tools for generating human-based in vitro brain models, namely neurospheroids. Extending the host laboratories' preceding research efforts to generate bi-partite (neurons + astrocytes) and tri-partite (neurons + astrocytes + microglia) human iPSC-derived neurospheroids, I hypothesize that subjection of mature tri-partite neurospheroids to stroke-like conditions (oxygen/glucose-deprivation), in combination with advanced single cell analysis tools and measurement of electrophysiological network activity, will aid to unravel biologically relevant cellular and molecular events in the context of stroke pathology. In this way, the combined cellular and molecular toolbox for neurospheroid culture, manipulation and analysis will in short term pave the way for novel fundamental studies unravelling new pathways and/or potential targets for neuroprotection or repair, and in long-term novel therapeutic approaches for patients with cerebral ischemia.

Researcher(s)

• Promoter: Ponsaerts Peter
• Fellow: Van Calster Siebe

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project