Behavior Of Brain Stem Cells Controlled By Cerebrospinal Fluid Signals

The choroid plexus is a network of blood vessels in each ventricle of the brain. It is derived from the pia mater and produces the cerebrospinal fluid.  The choroid plexus, unfortunately, has been ignored to some degree when it comes to brain research.  However, CSF turns to be an important regulator of adult neural stem cells, research indicates.

A new study led by Prof. Fiona Doetsch at the Biozentrum of the University of Basel, Switzerland has shown that signals secreted by the choroid plexus dynamically change during aging, and these different signals affect the behavior of aged stem cells.

In the adult brain, neural stem cell populations in various places throughout the central nervous system divide to give rise to neurons and glial cells throughout our lives. These stem cells reside in unique micro-environments (known as niches) that provide key signals that regulate stem cell self-renewal and differentiation. Stem cells in the adult brain contact the ventricles, which are cavities in the brain filled with CSF. CSF bathes and protects the brain and is produced by the cells of the choroid plexus.

Ventricular System of the Brain

Doetsch and her coworkers have shown that the choroid plexus is a key component of the stem cell niche, and that the properties of this stem cell niche change throughout life and affect stem cell behavior.

Doetsch’s group discovered that the choroid plexus secretes a cocktail of important signaling factors into the CSF. These CSF-secreted growth factors are important in stem cell regulation throughout life. As we age, the levels of stem cell division and formation of new neurons decrease. They also showed that although stem cells are still present in the aged brain, and have the capacity to divide, their ability to do so have significantly decreased.

Graphical abstract

“One reason is that signals in the old choroid plexus are different. As a consequence, stem cells receive different messages and are less capable to form new neurons during aging. In other words, compromising the fitness of stem cells in this brain region,” said Violeta Silva Vargas, first author of the paper that appeared in the journal Cell Stem Cell. “But what is really amazing is that when you cultivate old stem cells with signals from young fluid, they can still be stimulated to divide, behaving like the young stem cells.”

In the future, Doetsch and her group plans to tease out the composition of the signaling factors secreted by the choroid plexus.  They would also like to know how the composition of this growth factor cocktail changes as a result of changes in brain states and how these changes affect neural stem cells. This could provide new ways to understand brain function in health and disease.

“We can imagine the choroid plexus as a watering can that provides signals to the stem cells. Our investigations also open a new route for understanding how different physiological states of the body influence stem cells in the brain during health and disease, and opens new ways for thinking about therapy,” said Doetsch.

This work was published here: Violeta Silva-Vargas et al., “Age-Dependent Niche Signals from the Choroid Plexus Regulate Adult Neural Stem Cells,” Cell Stem Cell, 2016; DOI: 10.1016/j.stem.2016.06.013.

Living Cell Technologies Completes Cell Implants into Parkinson’s Patients

Living Cell Technologies (LCT) is a Australasian biotechnology company with offices in Australia and New Zealand. One of the products pioneered by LCT is NTCELL; a capsule coated with alginate (a porous compound extracted from seaweed) that contains clusters of choroid plexus cells from newborn pigs. NTCELL transplantation allows them to function as a biological factory that produces growth factors and other small molecules that promote new central nervous system growth and repair disease induced by nerve degeneration.

The choroid plexus is the structure in the brain that produces cerebrospinal fluid. These cells also filter wastes from the brain and keeps the brain free of debris and other potentially deleterious material. Choroid plexus cells not only produce cerebrospinal fluid, but also a range of neurotrophins (nerve growth factors) that have been shown to protect against neuron (nerve) cell death in animal models of disease.

Several papers have reported on the use of implanted NTCELL capsules in animal model systems. Luo and others used NTCELLs in nonhuman primates that suffered from chemically induced Parkinson’s disease. This paper reported that the transplanted encapsulated choroid plexus clusters significantly improved neurological functions in these monkeys with Parkinson’s disease (J Parkinsons Dis. 2013 Jan 1;3(3):275-91). An earlier paper also showed that implanted improved the neurological function of rodents with a chemically induced form of Huntington’s disease (Borlongan CV and others, Cell Transplant. 2008;16(10):987-92).

On the strength of these successful animal studies, LCT launched human clinical trials in patients with Parkinson’s disease. On December 15th of last year, LCT announced that the final patient had been successfully implanted in its Phase I/IIa clinical trial of regenerative cell therapy NTCELL for Parkinsons disease. These implantations required a minor surgical procedure, which took place at Auckland City Hospital

This Phase I/IIa clinical trial is being led by Dr. Barry Snow, and is an open-label investigation of the safety and clinical effects of NTCELL in Parkinson’s patients who no longer respond to current therapy. Dr. Snow is the leader of the Auckland Movement Disorders Clinic at the Auckland District Health Board but is also an internationally recognized clinician and researcher in Parkinson’s disease.

These patients will be carefully tracked for improvements in the control of movement and balance. LCT hopes to present the results on this clinical trial, which will last 29 weeks) at the 19th International Congress of Parkinson’s Disease and Movement Disorders in San Diego in June 2015.

Dr Ken Taylor, chief executive, notes that the success of the implant procedure means that the time scale for the LCT clinical program remains intact.

“The treatment phase of the trial has been completed on schedule. We believe NTCELL has the potential to be the first disease-modifying treatment for patients who are failing the current conventional treatment for Parkinson’s disease,” said Dr Taylor.

Even though this Phase I/IIa clinical trial is meant to test the efficacy of NTCELL in Parkinson disease patients, NTCELL also has the potential to be used in a number of other central nervous system indications such as Huntington’s, Alzheimer’s and other types of diseases that affect motor neurons.

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.