TIMP3 Secreted by Mesenchymal Stem Cells Protects the Blood Brain Barrier After a Traumatic Brain Injury


Mesenchymal stem cells (MSCs) are found in multiple tissues and locations throughout our bodies, and they have the ability to differentiate into bone, fat, cartilage, and smooth muscle. MSCs also have the ability to suppress unwanted immune responses and inflammation. Therefore, MSCs are prime candidates for regenerative medical treatments.

MSCs have been used to experimentally treat traumatic brain injury (for example, Galindo LT et al., Neurol Res Int 2011;2011:564089). One of the main concerns after traumatic brain injury is damage to the blood brain barrier (BBB). BBB damage allows inflammatory cells to access the brain and further damage it. Therefore, healing the damage to the BBB or protecting the BBB after a traumatic brain injury is vital to the brain after a traumatic brain injury.

After a traumatic brain injury, the vascular system suffers damage and begins to leak. When blood leaks into tissues, it tends to irritate the tissues and damage them. MSCs release a soluble factor known as TIMP3 (tissue metalloproteinase-3) that degrades blood-based proteins known to cause damage to tissues when blood vessels leak. TIMP3 production by MSCs can also protect the BBB from degradation after a traumatic brain injury.

Researchers from the University of Texas Health Sciences Center, UC San Francisco, and two biotechnology companies have examined the protective role of MSCs and one particular protein secreted by MSCs in protecting the BBB after traumatic brain injury.

Shibani Pati, from UC San Francisco, and his collaborators from the University of Texas, Houston, MD Anderson Cancer Center, Amgen, and Blood Systems Research Institute (San Francisco) used MSCs to staunch the increased permeability the BBB after a traumatic brain injury.

They used a mouse model in these experiments and induced traumatic brain injuries in these mice. Then they gave MSCs to some, and soluble TIMP3 to others, and buffer to another group as a control. They discovered that the MSCs mitigated BBB damage after a traumatic brain injury. However, they also found that soluble TIMP3 could also protect the BBB approximately as well as MSCs. This suggested that the TIMP3 secretion by MSCs is the main mechanism by which MSCs protect the BBB after a traumatic brain injury.

To test this hypothesis, Pati and his colleagues administered MSCs to mice that had experienced traumatic brain injury, but they also co-administered a soluble inhibitor to TIMP3. They discovered that this inhibitor completely abolished the ability of MSCs to protect the BBB after a traumatic brain injury. They also found that the main target of TIMP3 was vascular endothelial growth factor. Apparently after a traumatic brain injury, massive release of vascular endothelial growth factor causes the breakdown of BBB structures. TIMP3 degrades vascular endothelial growth factor, which prevents BBB breakdown.

These findings suggest that administration of recombinant proteins such as TIMP3 after a traumatic brain injury can protect the BBB and decrease brain damage. Clinical trial anyone?

Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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