Environmental Factor, April 2010, National Institute of Environmental Health Sciences
Benefits of Stem Cell Research
By Laura Hall
On March 18, Guang Hu, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lmc/stemcell/index.cfm), principal investigator of the Stem Cell Biology Group discussed how studying embryonic stem cells can lead to a greater understanding of embryonic development and disease mechanisms and lead to advances in gene therapy. The Laboratory of Molecular Carcinogenesis (LMC) Seminar Series talk, titled "RNAi Screen Identified Novel Players in Embryonic Stem Cell Self-Renewal," was hosted by Thomas Eling, Ph.D., of the Eicosanoid Biochemistry Group.
In his introduction, LMC Chief Trevor Archer, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lmc/index.cfm), told the capacity audience that Hu would "describe a new group of genes that are important for the process of stem cell renewal and pluripotency."
Tapping the potential of differentiation
Embryonic stem cells (ESCs) are derived from the inner cell mass of a very early developmental embryo stage. Unlike most cells, an ESC can change or differentiate into any type of cell - an ability called pluripotency. ESCs can also divide indefinitely without differentiating, giving them the capability of self-renewal. How ESCs are able to differentiate and self-renew is not well understood.
However, as Hu explained, understanding the molecular basis of ESC differentiation and self-renewal processes has great benefits. ESC differentiation serves as a good model to study the complex events that occur during embryonic development in mammals.
Knowledge gained from stem cell research can help to further regenerative medicine. Human induced pluripotent stem cells (iPSCs) are formerly differentiated somatic, or "normal," non-stem cells that have been induced or reprogrammed into an ESC-like state. Like ESCs, iPSCs can be induced to differentiate into a desired cell type allowing for the correction of genetic mutations that cause disease in patients.
In gene therapy, the corrected cells would be transplanted back into the patient to alleviate symptoms and hopefully prevent the expression of the disease. The iPSCs are a nearly identical match to the cell donor and would be unlikely to cause immune rejection problems - giving them great potential for regeneration of damaged tissue.
Studying ESCs can shed light on the derivation of iPSCs and the desired cell types for cell-based therapies. Also, for many diseases, such as amyotrophic lateral sclerosis, there are no cell culture models to study. This lack hinders research trying to identify possible disease mechanisms or drug targets. Deriving the cell types affected by the disease from stem cells "opens up a new window to investigate what is the cause, what is behind the symptoms," said Hu. Specific cells can also be derived and used for drug screening to find new drugs to treat disease effectively.
Hu and colleagues have screened the genome of mouse ESCs to identify genes that are needed to maintain self-renewal. In his talk he focused on two of the genes, CCR4-Not transcription complex subunit 1 (Cnot1) and subunit 3 (Cnot3). The Cnot complex regulates transcription, but different components of the complex appear to have different functions, and only Cnot1 and Cnot3 showed up as self-renewal genes.
When Hu knocked down the Cnot1 or Cnot3 genes in his mouse ESCs, he found that numerous differentiation marker genes were upregulated and the cells changed their morphology, or appearance, to look more like differentiated cells. However, the selected cells did not differentiate into specific cell type lineages, suggesting that the two Cnot genes were probably more involved in maintaining self-renewal rather than causing differentiation.
Hu plans to further test Cnot1 and Cnot3 by creating conditional knockout mice to see if these genes are important in embryonic development. Other studies in ESCs will identify the downstream targets of the two genes and the composition of the Cnot complex, and determine if Cnot1 and Cnot3 impact the initiation of pluripotency when adult cells are induced to become iPSCs.
Hu will also validate and study other genes identified in his screen to try to understand the molecular basis of self-renewal in ESCs.
(Laura Hall is a biologist in the NIEHS Laboratory of Toxicology and Pharmacology currently on detail as a writer for the Environmental Factor.)