Cholesterol Important For Brain Development, Study
The study, which is published in the 2 October issue of the journal Cell Stem Cell, was the work of researchers from Sweden, the US, Australia and the UK and was led by Professor Ernest Arenas of the Center for Developmental Biology and Regenerative Medicine at Karolinska Institute in Stockholm, Sweden.
One of the many challenges of using stem cells in medicine and research is how to control them so cell growth and proliferation does not get out of hand. Stem cell therapies have great potential as treatments for brain-wasting diseases such as Parkinson's disease, where motor function diminshes in line with decline in specialist brain cells that make the neurochemical dopamine which is essential for many brain processes, including motor skills and reward systems.
In this study, Arenas and colleagues used mice to show that to fuction properly, dopamine-producing brain cells depend on a chemical called oxysterol being able to activate a specific receptor. Oxysterol is an oxidised form of cholesterol.
They also found that treating lab-cultivated embryonic stem cells with oxysterol helped them make more dopamine-producing cells and reduced uncontrolled growth of the stem cells.
Arenas told the media that: "Oxysterol contributes to a safer and better cultivation of dopamine-producing cells, which is a great advancement since it increases the possibility of developing new treatments for Parkinson's disease."
For the study, the researchers looked at how oxysterol binding to two nuclear liver X receptors (Lxr-alpha and -beta) affected cell division, growth of cells in the ventral midbrain (VM neurogenesis), and development of dopamine-producing (dopaminergic, DA) neurons or nerve cells in mouse embryos.
When they deleted the liver X receptors it led to "reduced cell cycle progression and VM neurogenesis, resulting in decreased DA neurons at birth".
When they activated liver X receptors with oxysterol it led to increases in the dopamine-producing neurons in mouse embryonic stem cells and in wild-type VM progenitor cultures (but not in those where the receptors had been deleted).
When the researchers treated human embryonic stem cells with oxysterol, at the stage when they differentiate into dopamine-producing cells, they found that it increased production and number of mature dopamine-producing cells, "while reducing proliferating progenitors".
Arenas and colleagues concluded that using liver X receptor ligands or activators (like oxysterol) may improve embryonic stem cell treatments for Parkinson's disease by "selectively augmenting the generation of [dopamine-producing] neurons".
The researchers hope that one day it will be possible to replace the dead cells in the brains of Parkinson's patients with dopamine-producing cells grown in the lab. Such cultures could also be used to test new drugs for the disease.
"Liver X Receptors and Oxysterols Promote Ventral Midbrain Neurogenesis In Vivo and in Human Embryonic Stem Cells."
Paola Sacchetti, Kyle M. Sousa, Anita C. Hall, Isabel Liste, Knut R. Steffensen, Spyridon Theofilopoulos, Clare L. Parish, Carin Hazenberg, Lars Ährlund Richter,Outti Hovatta, Jan-Ake Gustafsson, and Ernest Arenas.
Cell Stem Cell, Vol 5, Issue 4, pages 409 - 419, 2 October 2009.
Source: Karolinska Institutet.
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