In this post I dip into some recent developments in the rapidly evolving field of stem cell research, this time focusing on embryonic stem (ES) cells.Today a news item appeared that reports a Spanish researcher has discovered a genetic circuit that regulates the differentiation behavior of embryonic stem cells(ref). As explained in the original article, “There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core.” Apparently the degree of expression of Nanog is in constant flux and only when this level is low is an ESC ready for differentiation. At any given time this is the case in only a small percentage (5% – 20%) of the available ESCs. “Our results show that a population of ES cells represents a dynamic distribution of related states fluctuating between a stable state of high Nanog expression (HN) and an unstable state of low Nanog expression (LN). We also observe that LN cells are prone to differentiate, and exhibit an increased variability in gene expression as well as low-level expression of differentiation markers(ref).” Previously it was thought that the differentiation availability of ESCs was homogeneous, all cells being in the same state of pluripotency, and it was thought that the cells that differentiated were those that received external differentiation signals, This is very interesting because the same three protein transcription factors (Sox2, Oct4, and Nanog) plus Lin28 can be used to cause any normal somatic cell to revert to IPSC (induced pluripotent stem cell) status. See the post on this blog Update on induced pluripotent stem cells. Apparently these same proteins are involved in a two-way street between pluripotent and differentiated cell status.
A related 2007 finding involves the self-renewal of ESCs. “The researchers found that Jmjd1a and Jmjd2c, which encode enzymes that demethylate histone H3 lysine 9, regulate self-renewal in mouse ES cells: Depletion of Jmjd1a and Jmjd2c promoted differentiation, at the expense of self-renewal. Thus, these two histone modifying enzymes are required for maintaining pluripotency of ES cells(ref).” Self-renewal vs differentiation of ES cells thus appears to be a matter of epigenetics. As long as Jmjd1a and Jmjd2c are around, histone methylation is nipped in the bud and the cell acquires no epigenetic history due to such methylation. Once methylation starts to take place the cell starts acquiring history and is prone to differentiation. See the blog entries Epigenetics, Epigenomics and Aging, DNA methylation, personalized medicine and longevity and Epigenomic complexity. Also, you can check the discussion of the Programmed epigenomic changes theory of aging in my Anti-Aging Firewalls treatise.
Whether we are concerned with embryonic stem cells or induced pluripotent stem cells, a key issue is how to get such pluripotent cells to differentiate into desired cell types including adult stem cells like hematopoietic stem cells or astrocytes or mesenchymal stem cells and then how to get these further to differentiate into the somatic cell types ultimately wanted. My impression is that there is a lot of work going on studying aspects of this issue. For example, this report is on work looking at the elacticity of a stem cell’s environment as a determinant of what type of somatic cell that stem cell becomes. “In laboratory tests, Dennis Discher and Adam Engler *researchers at the University of Pennsylvania) grew mesenchymal stem cells (derived from adult bone marrow) in polymer hydrogels with either soft, medium or rigid elasticity. Based on resulting cell shapes as well as messenger RNA and protein markers, stem cells grown in softer environments — such as brain tissue — tended to produce nerve-like cells; those grown in environments with medium elasticity — similar to muscle — produced muscle-like cells. — The stem cells grown in more rigid environments — like bone — produced bone-like cells(ref) .” There have been several successful attempts to get embryonic stem cells to differentiate into tissue-specific cells. For example, a research team in Sweeden “ has managed to establish and isolate the tissue-specific stem cell that produces blood cells (blood stem cell) by using genetically modified embryonic stem cells(ref).”
Another report is about using human ESCs to generate “natural killer” immune system cells that can can combat cancers. “This is the first published research to show the ability to make cells from human embryonic stem cells that are able to treat and fight cancer, especially leukemias and lymphomas,” — “We hear a lot about the potential of stem cells to treat conditions such as Parkinson’s disease, diabetes, and Alzheimer’s disease. This research suggests it is possible that we could use human embryonic stem cells as a source for immune cells that could better target and destroy cancer cells and potentially treat infections(ref).” Also see the blog post Dendritic cell cancer immunotherapy on Geron’s work producing dendritic cells on a large scale from ESCs for immunotherapy purposes. Besides research related to embryonic stem cells there is much research going on related to induced pluripotent stem cells and to adult somatic stem cells. I will continue to report selectively on important developments.