Generation of Merlin-Deficient Human Inner Ear Organoids to Model Neurofibromatosis Type 2 Pathogenesis
Abstract
Neurofibromatosis Type 2 (NF2) is a rare disease in which non-cancerous tumors form throughout the body. Although tumors do not form cancers, even slowly growing tumors can cause dysfunction due to the location in which these tumors often develop. The location of some of these tumors is on the nerve that carries information from the ear to the brain. The cell that gives rise to this type of tumor is called a Schwann cell. Schwann cells can be thought of as a type of rubber insulator that allows a neuron, which is similar to a metal wire, to conduct nerve impulses. In many NF2 patients, due to a specific genetic mutation, Schwann cells can begin to grow rapidly and divide more quickly than usual, ultimately forming a tumor. Since this tumor develops from Schwann cells, it is termed a Schwannoma, a mass of Schwann cells. Since Schwannomas are located so close to the nerve carrying information from the ear, they can cause problems like hearing loss, balance issues, pressure on parts of the brain, and neurological dysfunction. Currently, there are few treatment options available to halt the growth of a schwannoma outside of invasive surgical removal or radiation, which can involve significant complication. Our current knowledge of the development of these tumors in humans is limited due to the fact that, until now, research in the field has been restricted to experiments using mice, rats, and simple human cell culture models. Here, we will develop a new way to accurately mimic inner ear schwannoma formation. Our research group recently invented a method to produce inner ear cells from human stem cells in a culture dish. This ear-in-a-dish method generates many of the cells required for inner ear development and function, including Schwann cells and the neurons they insulate. For this project, we will create an ear-in-a-dish model using human cells that are very similar to NF2 patients’ own cells. They are similar because NF2 patients’ cells have a mutation in a gene that produces a protein called Merlin. Our hypothesis is that, if we can grow an ear-in-a-dish that has the same Merlin mutation as NF2 patients, then we can induce schwannoma formation in an environment that is very similar to the human body. Using this layered model, we will be able to assess what other cells are involved in schwannoma development. We could also do preliminary testing of potential new therapies in our model before testing them in NF2 patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910769
Entities
People
- Karl Koehler
Organizations
- Boston Children's Hospital
- United States Army