EBICS Leadership Title: EBICS Director
Academic Title-Position: Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering
Department: Biological Engineering, Mechanical Engineering
University: Massachusetts Institute of Technology
Research Lab: Kamm Lab | MechanoBiology Laboratory
Research Group Member: MPS Research Group
Contributing Trainee(s) and corresponding trainee projects: Tatsuya Osaki, Jean Carlos Serrano, Kristina Haase, Giovanni Offeddu, Yoojin Shin, Clare Ko
Microphysiological systems, or MPS, act as miniaturized versions of a human organ, and can be derived from induced pluripotent stem cells (iPSCs) obtained from a specific patient. They enable development of models of disease that can be used for testing new drugs, or precision medicine applications by producing a model of the disease in a given patient. Our EBICS research is addressing these needs through creating MPS for the central nervous system that include both cells of the brain tissue (neurons, astrocytes) and those comprising the brain vasculature. By combining these different cell types within a single MPS, we have generated models for amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and the pathway for drugs entering into the brain from the vascular system. In the ALS model, patient-derived cells from healthy donors and ALS patients were used to create a model of a neuromuscular junction that recreates the activation of a muscle strip by motor neurons. The value of the model was demonstrated by showing differences between healthy and ALS cells in the ability of the muscle to generate force upon activation by the motor neurons, then showing that the functional benefits of two new drugs under development can be recapitulated in the model.
For drugs of this type to be effective, however, they must be capable of passing from the blood across the blood-brain barrier (BBB) into the tissue of the brain or nervous system. To study transport across the BBB we developed a different MPS based entirely on human cells, including iPSC-derived vascular endothelial cells, pericytes, and astrocytes. We demonstrated how, over time, the endothelial cells took on characteristics of the cells found in the brain, showing increased expression of junctional proteins that comprise the barrier, and transporter proteins that enable trancytosis (transport through the endothelial barrier cells) of substances that the brain requires. This model and the results obtained from it will help us to identify ways in which we can ‘hijack’ these transporters to deliver new drugs for the treatment of ALS or other neurological diseases.
Figure Caption: Motor neurons on the left send out neurites (green) and connect with a strip of skeletal muscle (red) on the right.