A Multicellular, Human Pluripotent Stem Cell-Derived Platform to Study Neuroinflammation in Amyotrophic Lateral Sclerosis
Abstract
Inflammation of the brain and spinal cord has been identified as a driving factor in the progression of a wide range of diseases, including Chronic Traumatic Encephalopathy (CTE, recently associated with head trauma in football players) and many other neurodegenerative diseases. The immune and support cells of the brain (microglia and astrocytes, respectively) play important roles in maintaining the health and proper function of neurons (the cell type in the brain and the spinal cord that transmits information). However, sometimes these immune cells become aberrantly activated resulting in an inflammatory response that can cause neurons to die. This aberrant inflammatory response has been shown to play a particularly prominent role in the progression of Amyotrophic Lateral Sclerosis (ALS), also referred to as Lou Gehrig s disase. How this inflammation is regulated in the brain or spinal cord, however, is still largely unknown. All three cell types (microglia, astrocytes, and neurons) seem to be involved and may present promising targets for early therapeutic intervention. However, due to their complex interplay, accurate identification of such targets and prediction of their effects on the system as a whole requires studying them together. One problem has been the limited access to those cell types directly from human individuals, which has stalled progress for such studies. Therefore, there is a huge need for a human system to study neuroinflammation and to identify promising immunomodulatory therapies. Our plan is to develop a minimalist system in a Petri dish that can recreate the effects of inflammation in the brain and use this unique platform to identify drugs that can regulate over-activated immune responses such as in ALS. Human pluripotent stem cells (hPSCs) are a special type of stem cell that can grow in very large numbers and that can give rise to all the different cell types of the human body. Patient skin cells can be converted into hPSCs, resulting in a stem cell model that matches the exact DNA of an affected patient. Our research lab is highly experienced in taking such hPSCs and directing them into specific cell types of the brain. Recently, our laboratory has developed novel methods to make human astrocytes, microglia, and spinal motoneurons (the cell type that degenerates in ALS) from hPSCs. We can generate these cell types from hPSCs from both patients with ALS as well as from controls (individuals who do not have ALS) as comparison. We will then combine human motoneurons, astrocytes, and microglia from these patients in a dish to study two important parameters in the progression of ALS: markers of inflammation and cell death. Our system is derived completely from human cells, which is of particular importance because there are significant differences between species in how the immune system works. In fact, this may explain why many therapies found to successfully treat diseases in mice failed to translate in human patients. We will use our human cell-based system to overcome this therapeutic hurdle by using it as a powerful platform to test thousands of drugs in parallel that may regulate inflammation and that may prevent cell death of motoneurons. We hypothesize that the level of inflammation that we observe in a dish for a particular patient s cells will correlate with the level of inflammation in the disease of such patient. Therefore, in patient cells where the identified drugs prove to be beneficial in a dish, we expect that those compounds may likely provide therapeutic benefit to the patient as compared to drugs identified in mice or human cancer cell lines commonly used for such studies to date. Patients can respond to drugs differently from one another. We expect that our novel system will help predict individual patient responses as well. Once we verify candidate therapeutic targets that improve inflammation and survival of motoneurons across multiple parameters, we
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110140
Entities
People
- Lorenz Studer
Organizations
- Sloan-Kettering Institute
- United States Army