Can Regenerative Medicine Help Those with Traumatic Brain Injury?

The lingering effects of post-concussive syndrome, more technically called Traumatic brain injury (TBI) can be devastating for a sufferer and his or her family. Brain-related disabilities can occur when the head is struck or shaken (or both). This leads to structural damage of the soft brain tissues and their connections. As a result, a person may suffer related functional changes, and neurological deficits. The severity of TBI can range from mild, moderate, to severe, with symptoms ranging from headaches, dizziness, and confusion to seizures, paralysis, and coma. The terminology should be understood to be comparative, as even a “mild” traumatic brain injury can be associated with disabling symptoms (whereas a severe TBI sufferer may be a vegetable). Although acute TBI sufferers tend to show improvement in the early months, there has been no cure for chronic symptoms of TBI. Presently, the available treatments focus on supportive care and symptom management, and on compensation for what one can no longer do (stop working, get help with the checkbook, etc).

Traditionally, doctors were taught that TBI patients may show improvements for 12-18 months after brain injury by undergoing various types of retraining and therapy, through a process called “plasticity,” where under-used parts of the brain can take up duties of injured parts. However, recent advances in regenerative stem cell medicine have brought encouraging news through the use of exosomes (extracellular vesicles) and stem cells as a potential assistive approach to help address the lingering and previously considered permanent effects of TBI, even late after injury, or after the accumulation of multiple injuries.

To understand the basics of stem cell medicine, it is important to understand that “stem cells” have beneficial youthful properties. They divide into other types of cells needed in our bodies, both to create them and later to replenish them. When we were just a fetus in the womb, we were made up mainly of stem cells, all destined to grow and develop into a person. Stem cells (and all cells for that matter) communicate with their neighbor cells, so they can coordinate efforts. One cell can influence another, and then the influenced cell can influence its neighbors and so on. This coordinated cellular programming information from one cell to another occurs through small bodies, about 1/1000th the size of a cell, called exosomes.

These numerous exosomes are small extracellular vesicles that are secreted by various cells, including our stem cells, and contain a variety of signaling molecules, such as proteins, nucleic acids (usually RNA), growth factors, and lipids. They have been shown to play a critical role in cell-to-cell communication, including intercellular signaling and the transfer of biomolecules between cells. These delivered proteins and growth factors influence the genes that are being activated in a given cell. This is the leverage point in considering the potential benefits for using regenerative medicine to help address TBI: using the most youthful, regenerative signal to influence injured and degenerating brain and nerve cells. Exosomes derived from youthful stem cells have been shown to have therapeutic effects in various neurological conditions, including TBI, by re-invigorating the healing, regenerative, and anti-inflammatory machinery that exists within all of our cells.

The use of exosomes has been studied as a treatment for TBI. In a preclinical study published in the Journal of Neurotrauma, researchers found that intravenous injection of MSC (mesenchymal stem cells) derived exosomes in rats with TBI improved motor function, reduced brain inflammation, and enhanced neuroprotection. The authors attributed these effects to the anti-inflammatory and neurotrophic (nerve growth) properties of the exosomes. Similarly, another study published in Stem Cell Research & Therapy demonstrated that intravenous injection of exosomes derived from human umbilical cord MSCs in rats with TBI improved cognitive function, reduced brain edema, and enhanced angiogenesis (re-growth of blood vessels). These authors suggested that the therapeutic effects of the exosomes were due to their ability to modulate immune responses (reduce inflammatory damage), reduce oxidative stress, and promote tissue repair.

Stem cells, besides having regenerative properties, are also known to have neuroprotective properties. Several types of stem cells have been investigated for TBI, including MSCs, neural stem cells, and induced pluripotent stem cells. These cells can be found in bone marrow, adipose (fat) tissue, and the umbilical cord. They have been shown to have neuroprotective and anti-inflammatory effects and can differentiate into various cell types, including neurons and glial cells. In a study published in Stem Cells Translational Medicine, researchers found that intravenous injection of human bone marrow-derived MSCs in rats with TBI improved motor function, reduced brain inflammation, and enhanced neuroprotection. The authors suggested that the therapeutic effects of MSCs were due to their ability to secrete neurotrophic (nerve growth) factors and modulate immune responses (meaning suppress inflammation related to our immune system). MSCs and exosomes are both readily available biologics.

Neural stem cells, on the other hand, are a type of stem cell that can differentiate into various types of neural cells, including neurons, astrocytes, and oligodendrocytes. They have been shown to have the potential to replace damaged neural cells and promote neuroregeneration. In a preclinical study published in the Journal of Neurosurgery, researchers found that transplantation of neural stem cells in rats with TBI improved cognitive function and promoted neuroregeneration. The authors suggested that the therapeutic effects of neural stem cells were due to their ability to differentiate into neural cells and secrete neurotrophic factors. These types of cells are not yet available in the community. However, exosomes derived from MSCs can stimulate and activate cells of the neurological system.

Not yet available for use are Induced pluripotent stem cells (iPSCs). These are a type of stem cell that are generated by reprogramming somatic cells, such as skin cells, to a pluripotent state, allowing them to differentiate into various cell types, including neural cells. iPSCs have been shown to have potential in the treatment of various neurological conditions, including TBI. In a preclinical study published in Stem Cells Translational Medicine, researchers found that transplantation of iPSC-derived neural progenitor cells in rats with TBI improved motor function and promoted neuroregeneration. The authors suggested that the therapeutic effects of iPSCs were due to their ability to differentiate into neural cells and secrete neurotrophic factors.

When comparing exosomes and MSCs, one is easier to deliver to the brain than the other. Stem cells when delivered intravenous (IV) do not readily cross the blood brain barrier, whereby exosomes do. Stem cells would require direct delivery to the spinal fluid or brain to get into the nervous system. Exosomes are much smaller and can penetrate into the nervous system and into tissues much more reliably.

TBI is a devastating condition that currently has no cure. However, recent advances in regenerative medicine have shown promise mainly through the use of IV exosomes, at present. In multiple studies, exosomes and stem cells have been shown to have therapeutic effects including improved motor function, reduced brain inflammation, and enhanced neuroprotection. We can expect more advances and more experience in the coming months and years. There is hope for those who suffer.