Fibrinogen – Fewer Scars In The Central Nervous System

The influence of the coagulation factor fibrinogen on the damaged brain has been detailed by scientists at the University of Freiburg in a news paper.

Neural stem and progenitor cells (NSPCs), from the so-called subventricular zone (SVZ), can help to repair a brain damaged by central nervous system disorders. It is known that the microenvironment within the SVZ directs the differentiation of stem and progenitor cells (NSPCs) toward cells in the nerve tissue.

However, researchers have not yet been able to explain why NSPCs do not develop into neurons after injuries to the central nervous system, but rather into astrocytes.

Regeneration Of Nerves

Astrocytes play a major role in the formation of scars and thus interfere with the regeneration of the nerves in the central nervous system. A team led by Prof. Dr. Christian Schachtrup and Lauriane Pous from the Faculty of Medicine has now succeeded in analyzing a further step in these processes in the brain.

“The discovery that an important blood coagulation protein, fibrinogen, can induce an astrogenic milieu in the SVZ stem cell niche, which determines the contribution of NSPCs to repair mechanisms in CNS diseases, has potential implications for several processes in CNS diseases in different stem cell niches,”

says Schachtrup.

Fibrinogen

Fibrinogen is a blood coagulation factor and a precursor of the protein fibrin, which coats and stabilizes the blood platelets that gather at the site of a vascular injury. Fibrinogen inhibits the neuronal differentiation of NSPCs, the researchers discovered.

At the same time, the enriched fibrinogen leads to increased astrogenesis, i.e. the formation of new astrocytes, as fibrinogen activates the so-called BMP receptor signaling pathway. By experimentally reducing fibrinogen, for example by adding the snake venom Ancrod, the astrocyte formation from NSPCs was blocked, which is why only reduced scars developed.

NSPCs of the SVZ
In the healthy brain, NSPCs of the SVZ continuously generate mobile DCX+ neuroblasts that migrate through the rostral migratory stream to the olfactory bulb to become newborn neurons.
Cortical injury results in increased SVZ vasculature permeability and fibrinogen deposition into the SVZ stem cell niche environment. Fibrinogen activates BMP receptor signaling via its αC domain inducing NSPC differentiation into neuroprotective astrocytes, which migrate towards the cortical lesion area and secrete Thbs4.
Local provisional fibrinogen thus activates BMP signaling in NSPCs inducing their differentiation into astrocytes at sites of vascular permeability in the CNS. CSF cerebrospinal fluid, NSPCs neural stem/precursor cells, RGD Arg–Gly-Asp sequence (integrin binding site), SVZ subventricular zone.
Credit: The Astrocyte image was adapted from http://togotv.dbcls.jp/ja/togopic.2011.17.html, under Creative Commons Attribution 4.0 International (CC BY 4.0) license. The original astrocyte image was designed by Hiromasa Ono. The Brain image was adapted from https://icon-icons.com/de/symbol/Gehirn/39333, under Creative Commons Attribution 4.0 International (CC BY 4.0) license. The original brain image was designed by Lorc, Delapouite & contributors.

Schachtrup and his team showed that, following damage to the cerebral cortex of mice, fibrinogen from the blood is enriched in the stem cell niche of the SVZ, which is located further inside the brain.

The work was supported by an International Graduate Academy Fellowship, a Deutscher Akademischer Austauschdienst fellowship, a Fazit Foundation Graduate fellowship, the Department of Defense, NIH/NINDS, the European Commission, and the German Research Foundation.

[1] Pous, L., Deshpande, S. S., Nath, S., Mezey, S., Malik, S. C., Schildge, S., Bohrer, C., Topp, K., Pfeifer, D., Fernández-Klett, F., Doostkam, S., Galanakis, D. K., Taylor, V., Akassoglou, K., Schachtrup, C. (2020) Fibrinogen induces neural stem cell differentiation into astrocytes in the subventricular zone via BMP signaling. Nature Communications 11, 630, S. 1-13. DOI: 10.1038/s41467-020-14466-y

Top Image: The blood clotting protein fibrinogen (red) is deposited in the stem cell niche and regulates the contribution of stem cells (green) to repair mechanisms in central nervous system diseases. Photo: Schachtrup lab / University of Freiburg


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