‘Mini-brain’ models point to poorer oligodendrocyte growth in PPMS

Using stem cells derived from people with multiple sclerosis (MS), researchers developed cerebral organoids, or “mini-brains,” to better study the cellular and molecular mechanisms leading to the neurodegenerative disorder.

Initial analysis showed that patient-derived stem cells, especially those from people with primary progressive MS (PPMS), tend to be less able to grow into myelin-making cells called oligodendrocytes. These stem cell abnormalities were linked to a strong decrease in p21 protein levels, which affects cell growth, in PPMS patients.

Findings imply that an individual’s genetic background may affect MS onset and progression by altering the activity of oligodendrocytes, the researchers said.

The study, “Cerebral organoids in primary progressive multiple sclerosis reveal stem cell and oligodendrocyte differentiation defect,” was published in Biology Open.

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Cell models to understand better how genetics might affect MS

MS is caused by inflammation in the brain and spinal cord that damages the myelin sheath, a fatty covering around nerve fibers that helps them send electrical signals.

An individual’s genetics are broadly thought to influence the risk of developing MS and how the disease progresses, but the role of genetics in MS remains poorly understood.

To gain insight into how genetics affects MS, a team of scientists at the Tisch MS Research Center developed a novel cell model of the disease. For the model, the scientists collected blood cells from healthy people and those with various types of MS.

Then, through a series of biochemical manipulations, the blood cells were reprogrammed into induced pluripotent stem cells, or iPSCs, which are lab-made stem cells able to grow into other types of cells. These iPSCs were used to grow cerebral organoids, “mini-brains” containing cells arranged in a 3D architecture that resembles how the cells would be arranged in the human nervous system.

Because the iPSCs retain the genetic code of the person that the blood cells are originally isolated from, this model “provides insight into the effect of patient genetic background on neural cells and their interactions in a model free of immune system interaction and within a controlled microenvironment,” the researchers wrote.

“Our innovative cerebral organoids address a persistent challenge for MS researchers worldwide, and represent a major step forwarding in advancing our knowledge of cellular dysregulation,” Saud A. Sadiq, MD, a neurologist and director of the Tisch center, and a study author, said in a press release from the center.

“Since MS is a human-specific disease, this application of our cerebral organoids is absolutely critical in giving MS research the ability to conduct analysis on human tissue,” added Nicolas Daviaud, PhD, a neuroscientist and assistant research scientist at Tisch and the study’s lead author.

Of note, the organoids contain both neurons (nerve cells) as well as glia, which are a class of neurological cells that help to support nervous system function. For example, oligodendrocytes are a glial cell subset chiefly responsible for making myelin in the brain and spinal cord.

Stem cells in MS organoids less efficient at growing into new cell types

After growing the organoids for six weeks, the researchers found that those derived from people with MS tended to have lower overall rates of cell growth. This was particularly evident in models derived from people with the primary progressive form of the disease.

More specifically, MS organoids had a slightly increased growth of cells into neurons, but reduced growth of cells into oligodendrocytes and other types of glia.

Further analyses suggested that MS organoids, especially those from PPMS patients, had less “stemness” — that is, stem cells in these models were less efficient at growing into new types of cells.

This lack of stemness and the associated changes in growth in MS organoids linked with lower levels of a protein called p21, which is known to play an important role in regulating cell growth and division.

Findings imply that genetic differences among people with MS, especially PPMS, might lead to lower oligodendrocyte activity. This may contribute to poorer myelin repair in MS, which is often seen as the disease progresses, the researchers said.

The scientists hope their organoid models will serve as a useful tool for future studies, and in understanding how a person’s genetic background influences MS development.

“This work provides new insights on the innate cellular dysregulation in MS and identifies p21 as a new protein of interest. Hopefully, this novel technology will open the path to future therapeutic approaches and a long-awaited cure for patients with MS,” Daviaud said to Multiple Sclerosis News Today in an email.

“We look forward to building on the findings of this research to study the mechanisms and various pathways leading to the differences we observed, allowing us to develop an improved understanding of the [mechanisms] of MS,” he added.