Strategieën om betrouwbare microvasculaire endotheelcellen uit de hersenen te maken uit pluripotente stamcellen

We will develop a novel 3D human brain tissue-like model on-chip to unravel the mechanisms underlying neurodegeneration in Alzheimer's disease. Abstract: Alzheimer's disease (AD) is the number one cause of dementia worldwide. It causes progressive neuronal death causing progressive decline in cognitive and behavioral functions. AD remains incurable, partly due to lack of preclinical models that fully recapitulate the human disease, and because the multifactorial nature of AD is still not fully understood. In the '3D-PADchip' project, we will develop a 3D AD-brain model on a microfluidic chip that better approximates the complexities of AD disease. Different human brain cells derived from induced pluripotent stem cells (iPSC) will be cultured in novel, synthetic, brain-specific hydrogel 3D microenvironments to recreate the complex makeup of the brain tissue. This gel-laden brain tissue will be incorporated in a micropatterned microfluidic device, to create a vascular network within the 3D brain tissues, and the formation of a perfusable human blood-brain-barrier (BBB). This 3D perfusable and vascularized human brain model will be transformed into AD-on-chip model by using AD-diseased iPSC-derived brain cells. If successful, we anticipate that this novel human '3D perfusable AD-on-Chip' model will enable addressing the following important scientific questions that remain to be elucidated regarding the pathogenesis underlying AD: (i) Do mutations in cortical neurons (which cause Amyloid-ß deposition and neuronal death) and/or microglia (causing inflammation and subsequent neuronal death) result in pathological changes in the BBB thought to contribute to progression of AD phenotypes; (ii) Does vascular dysfunction at the BBB initiate a cascade of events causing neuronal injury and as a consequence dementia. This project will open up new avenues for gaining insights into AD pathogenesis and developing new therapies for AD, and possibly other dementias.