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Posts Tagged ‘iPS cells

epigenetics and imprinting 3: at the beginning

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stuff that can be done with iPS cells

A zygote is the union of two gametes (haploid cells), the sperm and the egg. It’s the first diploid cell, from which all the other diploid cells – scores of trillions of them – are formed via mitosis.

What’s interesting about this from an epigenetic perspective is that gametes are specialised cells, but zygotes are essentially totipotent – the least specialised cells imaginable – and all this has to do with epigenetics.

I’m not entirely clear about what happens to turn specialist gametes into totipotent zygotes, and that’s what I’m trying to find out. I’m not sure yet whether zygotes immediately start differentiating as they divide and multiply or whether the first divisions – in what is called the zygote phase, which eventually forms the blastocyst – form an identical set of zygotes. 

The two-week period of these first divisions is called the germinal phase. During this phase zygotes divide mitotically while at the same time moving, I’m not sure how, from the fallopian tube to the uterus. Apparently, after the first few divisions, differentiation starts to occur. The cells also divide into two layers, the inner embryo and the outer placenta. The growing group of cells is called a blastocyst. The outer layer burrows into the lining of the uterus and continues to create a web of membranes and blood vessels, a fully developed placenta.

But, as Nessa Carey would say, this is a description not an explanation. How does this initial cell differentiation – into the outer layer (trophectoderm), which becomes the placenta and other extra-embryonic tissues, and the inner cell mass (ICM) – come about? Understanding these mechanisms, and the difference between totipotent cells (zygotes) and pluripotent cells (embryonic stem cells) is clearly essential for comprehending, and so creating, particular forms of life. This PMC article, which examines how the trophectoderm is formed in mice, demonstrates the complexity of all this, and raises questions about when the ‘information’ that gives rise to differentiation becomes established in these initial cells. Note for example this passage from the article, which dates to 2003:

It is now generally accepted that trophectoderm is formed from the outer cell layer of the morula, while the inner cells give rise to the ICM, which subsequently forms the epiblast and primitive endoderm lineages. What remains controversial, however, is whether there is pre-existing information accounting for these cell fate decisions earlier than the 8-cell stage of development, perhaps even as early as the oocyte itself. 

The morula is the early-stage embryo, consisting of 16 totipotent cells. The epiblast is a slightly later differentiation within the ICM. An oocyte is a cytoplasm-rich, immature egg cell.

Molecular biologists have been trying to understand cell differentiation by working backwards, trying to turn specialised cells into pluripotent stem cells, mostly through manipulating their nuclei. You can imagine the benefits, considering the furore created a while back about the use of embryonic stem (ES) cells in medical treatments. To be able to somehow transform a liver or skin cell into this pluripotential multi-dimensional tool would surely be a tremendous breakthrough. Most in the field, however, considered such a transformation to be little more than a pipe-dream.

Carey describes how this breakthrough occurred. Based on previous research, Shinya Yamanaka and his junior associate Kazutoshi Takahashi started with a list of 24 genes already found to be ‘pluripotency genes’, essential to ES cells. If these genes are switched off experimentally, ES cells begin to differentiate. The 24 genes were tested in mouse embryonic fibroblasts, and, to massively over-simplify, they eventually found that only 4 genes, acting together, could transform the fibroblasts into ES-type cells. Further research confirmed this finding, and the method was later found to work with non-embryonic cells. The new cells thus created were given the name ‘induced pluripotent stem cells’, or iPS cells, and the breakthrough has inspired a lot of research since then.

So what exactly does this have to do with epigenetics? The story continues.

Written by stewart henderson

January 6, 2020 at 5:28 pm