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Do metabolites regulate embryo development?
The recent findings should improve scientists' ability to use embryonic stem cells to grow new tissues and organs to replace those damaged by disease or injury. The findings also could lead to new treatments for common disorders ranging from infertility to cancer.
The researchers reported on their study in the Nov. 16 issue of the journal Nature Cell Biology.
After fertilization, a human egg begins to travel down the fallopian tube. As it does, it begins to divide to form a ball of embryonic cells. Each of these cells, called naive pre-implantation embryonic cells, has the capacity to develop into any cell type in the human body — an ability called pluripotency.
When the developing embryo enters the uterus, it must implant into the uterine lining if the pregnancy is to proceed. When this occurs, the naive stem cells undergo a critical change as they take the first step toward differentiating into specific cell types, such as gut, muscle or nerve cells. Such cells are called primed embryonic stem cells.
Scientists in the field of tissue regeneration are particularly interested in this shift from naive to primed embryonic stem cells. Although primed, post-implantation embryonic stem cells can still turn into any type of human cell, they are more difficult to work with than pre-implantation or naive cells.
To find out more about the differences between naive and primed pluripotent cells, the UW researchers first compared their gene profiles. This work conducted by Yuliang Wang, now a senior research associate at Oregon Health & Science University, uncovered intriguing differences in genes affecting cell metabolism.
To determine the effect of these changes, Henrik Sperber, a graduate student in the Ruohola-Baker laboratory, used a technique called mass spectroscopy to compare levels within cells of the metabolites.
The telltale metabolite found to be enriched in naive cells was methylnicotinamide, abbreviated MNA and a product of the metabolic enzyme whose levels increase in many cancers — nicotinamide N-methyltransferase or abbreviated as NNMT.
When active, NNMT consumes a methyl group from a compound called S-adenosyl methionine. This methyl group is normally used in a gene regulation process called epigenetic histone methylation.
Without an adequate supply of the S-adenosyl methionine, regulation by histone methylation — and therefore correct gene expression — cannot take place.
In the primed cells, on the other hand, NNMT activity was low. As a result, S-adenosyl methionine was available for these epigenetic modifications that are required for a cell to enter the primed state.
In fact, by knocking out specific genes through CRISPR gene-editing technology, Julie Mathieu, acting instructor in Ruohola-Baker laboratory, demonstrated that it was possible to stabilize the cells in either the primed or naive state by manipulating NNMT activity alone.
For example, such an approach might eventually form the basis for treating the most common cause of infertility — failure of the embryo to successfully implant — or for affecting cell changes leading to cancer.
This work was supported by the American Heart Association, The Ellison Medical Foundation, the Schultz Fellowship for Health Sciences, the National Institutes of Health, and the National Heart Lung and Blood Institute Progenitor Cell Biology Consortium.