Uncovering the role of Schwann cells in ALS pathogenesis

Our research aims to understand how nerves facilitate complex communication between different organs in the body, such as the gut and the brain. By studying these interactions, we hope to uncover how nerves regulate essential physiological processes and contribute to complex neurological disorders. We plan to achieve this by developing advanced stem cell-based models of the human nervous system. These unique models will revolutionize our ability to study nerve functions and interactions, driving research forward in groundbreaking ways.

A key focus of our work is on the crucial roles that glial cells play in these biological processes. Glial cells serve as vital gateways between the nervous system, the immune system, and other tissue components. Historically underappreciated in neurodegenerative disease research, where the focus has predominantly been on neurons, glial cells are now recognized as essential to understanding these diseases. By better understanding the roles of glial cells, we aim to unlock new ways of thinking about diseases and developing novel therapies.

Dr. Faranak Fattahi is an Assistant Professor in Cellular and Molecular Pharmacology at UCSF. Dr. Fattahi earned her PhD degree in Biochemistry, Cell and Molecular Biology at Weill Cornell Medicine and Memorial Sloan Kettering Institute in 2017, working in the lab of Dr. Lorenz Studer. After completing her PhD, she launched her independent lab at UCSF as a Sandler fellow and is currently an Assistant Professor at the UCSF Department of Cellular and Molecular Pharmacology and the Institute for Regeneration Medicine. The Fattahi Lab pioneers the use of human pluripotent stem cells to create intricate models of the peripheral nervous system. These models integrate diverse cell types and stimulation techniques, enabling in-depth studies of nerve-tissue crosstalk in development and disease. They are instru¬mental in understanding complex peripheral neuropathies and have applications in drug discovery and regenerative medicine.

Our research focuses on understanding the role of Schwann cells in the development of Amyotrophic Lateral Sclerosis (ALS), a devastating disease that leads to the degeneration of motor neurons. Traditionally, research has focused primarily on neurons, often overlooking the critical contributions of glial cells like Schwann cells. These cells, found in the peripheral nervous system, play an essential role in supporting and protecting motor neurons, which are crucial for voluntary muscle control.

 Despite their importance, Schwann cells have been relatively understudied in ALS research, partly due to the difficulty in accessing them from primary tissues. However, we have recently established a new strategy to generate Schwann cells from human pluripotent stem cells (hP3Title + textaddexpandmore-dots Title Textparagraphheaderheader-2header-3bolditaliclinkuloltableundoredoOur research focuses on understanding the role of Schwann cells in the development of Amyotrophic Lateral Sclerosis (ALS), a devastating disease that leads to the degeneration of motor neurons. Traditionally, research has focused primarily on neurons, often overlooking the critical contributions of glial cells like Schwann cells. These cells, found in the peripheral nervous system, play an essential role in supporting and protecting motor neurons, which are crucial for voluntary muscle control. Despite their importance, Schwann cells have been relatively understudied in ALS research, partly due to the difficulty in accessing them from primary tissues. However, we have recently established a new strategy to generate Schwann cells from human pluripotent stem cells (hPSCs). These lab-grown Schwann cells closely mimic their natural counterparts, providing a valuable tool for disease modeling and drug discovery. We successfully used these hPSC-derived Schwann cells to create a human cell-based model of Diabetic Peripheral Neuropathy (DPN). This model has helped us identify compounds that can mitigate nerve damage, demonstrating the potential of these cells in medical research. Building on this success, we aim to explore the role of Schwann cells in ALS using advanced techniques to examine the molecular and cellular changes in Schwann cells derived from ALS patient stem cells. Additionally, we will investigate how these changes in Schwann cells impact the function of neurons with which they interact.

Our innovative approach includes using cutting-edge single-cell gene expression analysis to understand the diversity of Schwann cell subtypes and their unique roles in ALS. We will also employ advanced co-culture systems to study the interactions between Schwann cells and neurons, and use techniques like multi-electrode array analysis to investigate the electrical activity of neurons. This research is poised to uncover new insights into the mechanisms driving ALS and to identify potential therapeutic targets, ultimately contributing to the development of new treatments for ALS patients. The support from The Pershing Square Foundation is crucial in facilitating this groundbreaking research. CTA label CTA URLSCs). These lab-grown Schwann cells closely mimic their natural counterparts, providing a valuable tool for disease modeling and drug discovery. We successfully used these hPSC-derived Schwann cells to create a human cell-based model of Diabetic Peripheral Neuropathy (DPN). This model has helped us identify compounds that can mitigate nerve damage, demonstrating the potential of these cells in medical research.

Building on this success, we aim to explore the role of Schwann cells in ALS using advanced techniques to examine the molecular and cellular changes in Schwann cells derived from ALS patient stem cells. Additionally, we will investigate how these changes in Schwann cells impact the function of neurons with which they interact. Our innovative approach includes using cutting-edge single-cell gene expression analysis to understand the diversity of Schwann cell subtypes and their unique roles in ALS. We will also employ advanced co-culture systems to study the interactions between Schwann cells and neurons, and use techniques like multi-electrode array analysis to investigate the electrical activity of neurons.

This research is poised to uncover new insights into the mechanisms driving ALS and to identify potential therapeutic targets, ultimately contributing to the development of new treatments for ALS patients. The support from The Pershing Square Foundation is crucial in facilitating this groundbreaking research.