In many nervous system diseases, such as multiple sclerosis (MS), spinal cord injuries, stroke, neonatal brain injuries, and even Alzheimer's disease, the brain loses the ability to repair the protective myelin that coats neuronal axons. It has been proposed that this process, known as remyelination, may be affected by blood components that can cross the blood-brain barrier. In a recent study, researchers led by a team from Gladstone Institutes in San Francisco have identified fibrinogen, a blood-clotting protein, as an inhibitor of remyelination.
In in vitro experiments, the team finds that fibrinogen, a coagulation factor, activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells. These are the key types of cells that ultimately develop to produce the myelin sheaths around axons. Activation of the BMP pathway effectively inhibits the proper differentiation of the progenitors into myelinating oligodendrocytes. Moreover, fibrinogen appears instead to promote a cellular fate that turns the progenitors into astrocytes.
"We found that fibrinogen stops adult stem cells from transforming into the mature cells that produce myelin," explained first author of the study Mark Petersen, MD. "This blockade could be harmful for regeneration in the brain."
Accordingly, inhibiting the activation of BMP signaling using an inhibitor protein, or by CRISPR/Cas9 knockdown of a key receptor rescues the effects caused by fibrinogen. Finally, therapeutic depletion of fibrinogen in vivo decreases BMP signaling and results in enhanced remyelination. These findings, published today in Neuron, thus identify fibrinogen a potential therapeutic target to promote the regenerative potential of neural progenitors in diseases involving remyelination.
"We thought it might be important to look instead at the toxic environment outside the cell, where blood proteins accumulate" said senior investigator Katerina Akassoglou, Ph.D. "We realized that targeting the blood protein fibrinogen could open up the possibility for new types of therapies to promote brain repair."
Image: Fibrinogen, the inactive form of fibrin, is soluble in water and is found in high concentrations in the blood. Image courtesy of David Goodsell / PDB-101.