New Cell Type Derived from Embryonic Stem Cells for Possible Treatment of Brain Diseases

This story comes from my alma mater, UC Irvine. Go anteaters!! No really, UC Irvine’s mascot is the anteater, not to be confused with the aardvark.

Edwin Monuki at the Sue and Bill Gross Stem Cell Research Center with his graduate student Momoko Watanabe and other colleagues devised culture conditions to differentiate embryonic stem cells in “choroid plexus epithelial cells.” Monuki and he team were able to make choroid plexus epithelial cells (CPECs) from mouse and human embryonic stem cell (ESC) lines.

Now you are probably reading this and screaming, “what the heck are CPECs?” Calm down, we will explain:

The central nervous system is surrounded by a clear fluid known as cerebrospinal fluid or CSF. CSF flows all around the brain and spinal cord and also flows inside it. The CSF has several functions. These functions include buoyancy, protection, stability, and prevention of stroke (ischemia).

The CSF provides buoyancy to the brain, since the brain is large a potentially heavy. However, by filling the brain from within and around it with CSF decreases the density of the brain. CSF allows the brain to maintain a density that prevent it from collapsing under its own weight. If the brain were denser, then it would compact and cut off the blood supply of the cells in the lower part of the brain. This would kill off neurons.

Protection provided by the CSF comes during those times the head is struck. The CSF prevents the brain from coming into contact with the skull. The stability provided by the CSF

CSF flows throughout the inside of the brain through cavities known as “ventricles.” These ventricles provide reservoirs through which the CSF flows and is absorbed back into the bloodstream. This constant movement of the CSF through the CNS rinses it and removes metabolic wastes from the central nervous system. It also guarantees an even distribution of neural materials through the central nervous system.

CSF also helps prevent strokes, since the low pressure of the CSF in the skull translates into low intracranial pressure, which facilitates blood perfusion.

Now that have seen that CSF is very important in the life of the brain, where does it come from?  The answer is the CPECs make CSF as a fine filtrate from blood plasma. A minority of the CSF is also made by the walls of the brain ventricles. Nevertheless, CSF circulates from the lateral ventricles to the interventricular foramen, to the third ventricle, through the cerebral aqueduct, to the fourth ventricle, through the median aperture and lateral apertures to the subarachnoid space over the brain and spinal cord where arachnoid granulations return the CSF to the bloodstream.

Thus, CPECs make CSF, which helps remove metabolic wastes and other toxic compounds from the brain. In various neurodegenerative diseases, the choroid plexus and CPECs degenerate too and fail to efficiently remove debris and other rubbish from the central nervous system. Transplantation experiments in rodents have demonstrated that implanting a healthy set of CPECs can restore CSF function and slow down the damage done to the brain by neurodegenerative diseases (see Matsumoto et al., Neurosci Lett. 2010 Jan 29;469(3):283-8).  The problem is the lack of good cultures of CPECs.

Monuki and Watanabe and company seem to have fixed this problem. Monuki commented on his publication, “Our method is promising, because for the first time we can use stem cells to create large amounts of these epithelial cells (CPECs), which could be utilized in different ways to treat neurodegenerative diseases.” Monuki is an associate professor of pathology and laboratory medicine and cell and developmental biology at UC Irvine.

To make CPECs from ESCs, Monuki and his team differentiated cultured ESCs into neural stem cells. The neural stem cells were then differentiated into CPECs. This strategy makes a great deal of sense, since a neural stem cell population seems to exist in the CPECs (see Itokazu Y et al., Glia. 2006 Jan 1;53(1):32-42.

According to Monuki, there are three ways that these cells could be used to treat neurodegenerative diseases. First, the CPECs could be used to make more CSF and that would help flush out the proteins and other toxic compounds that kill off neurons. The down side of this is that it would also increase intracranial pressure, which is not optimal. Secondly,. the CPECs could be engineered into superpumps that transport high concentrations of therapeutic agents into the brain. Third, cultured CPECs could be used as a model system to screen drugs and other agents that shore up the endogenous CPECs in the patient’s brain.

Monuki’s next step is to develop an effective drug screening system in order conduct proof-of-concept studies to determine how CPECs afect the brain in mouse models of Huntington’s disease and other pediatric neurological diseases.