The role of glial cells of the central nervous system in the maintenance of autonomic inflammation and the progression of multiple sclerosis (MS) is an important aspect of investigation. Therefore, the research team, led by neuroscientist Marina Absintha, PhD, from the IRCCS San Raffaele Scientific Institute in Milan, has developed forebrain organoids with neurons, astrocytes, oligodendroglia and - for immunocompetence - microglia derived from human induced pluripotent stem cells.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that can affect the entire brain and spinal cord. With regard to the disease mechanisms, it is now clearly established that it is an autoimmune disease. Although the causes of multiple sclerosis are not yet known in detail, there is a genetic component with a large number of immunologically relevant genes as well as environmental factors that play a role. Symptoms often include sensory disturbances, paralysis, impaired vision and balance and fatigue. In the course of the disease, depression, bladder and rectal disorders, pain, spasticity and cognitive impairment also occur.
Graphic: Computer-generated

Over a period of eight weeks, the organoids reproducibly formed mature cell types of the central nervous system. They exhibited cellular transcriptional profiles similar to those of the adult human brain. The organoids were then exposed to inflammatory cerebrospinal fluid from MS patients. This allowed the observation of the neurodegeneration: The cell types of the model correctly mimicked the neurodegenerative macroglia-microglia phenotypes as well as the intercellular communication in chronically active multiple sclerosis. Oligodendrocytes had already decreased by almost 50 % on the 6th day after exposure.

Using the simplified, three-dimensional in vitro platform, the researchers aim to progressively expand their understanding by testing hypotheses derived from human association studies. The scalability of hiPSC-derived organoids also enables the screening of genetic aspects to identify the most important key regulators of human myelination.  

Although the model has been thoroughly characterized so far, the studies have been limited to five different cell lines derived from two non-neurological controls and three MS cases. An expansion of the number of donors is being envisaged, in particular to assess morphological and transcriptional differences between MS patients and control subjects.

The scientific team is convinced that their MS inflammation model may be suitable for future drug screening with the aim to stop inflammatory neurodegeneration in MS patients.

Original publication:
Fagiani F, Pedrini E, Taverna S, Brambilla E, Murtaj V, Podini P, Ruffini F, Butti E, Braccia C, Andolfo A, Magliozzi R, Smirnova L, Kuhlmann T, Quattrini A, Calabresi PA, Reich DS, Martino G, Panina-Bordignon P, Absinta M. A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis. Cell Rep Med. 2024 Aug 20;5(8):101680. doi: 10.1016/j.xcrm.2024.101680. Epub 2024 Aug 8. PMID: 39121861.