Definition and assessment of totipotency

by Alexey Bersenev on May 14, 2014 · 0 comments

in embryonic/iPS

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We are hearing term “totipotent” in scientific literature all the time. Many people believe that embryonic stem cells (ESC) or iPS cells are totipotent. The most frequent definitions of “totipotency” that we can see in literature include:

  • cells which are capable to develop in whole embryo;
  • cells which are capable to differentiate into any type of cell and tissue of mature organism;
  • cells which are capable to generate embryonic tissues and extraembryonic membranes;

Unfortunately none of these definitions are scientifically correct. Maureen Condic, in her recent review, explains why. This is the best discussion piece that I’ve ever read on the topic! She gives a correct definition of totipotency –
Capability of single cell to produce fertile adult organism

Only two type of cells can fit “totipotency” definition – (1) zygote and (2) early-stage blastomeres (2-4 cell stage). The proper test for totipotency is implantation of single cell (zygote/ blastomere) in appropriate environment (uterus), leading to development of fully mature fertile adult organism. Unfortunately this test is very hard to perform. Such experiments, used cells isolated from inner cell mass of blastocyst, failed in developing an embryo. As of today, there are no reports on spontaneous generation of embryos from single ESC.

Two assays – blastocyst complementation and embryo chimerization, which frequently cited as tests for totipotency, actually assess pluripotency. In this case ESC or iPS will contribute to embryo development, but will not originate it on its own. Obviously, conclusions about toti- or pluripotency can not be solidified, based only on markers expression.

While injected stem cells make minor contributions to placenta and membranes in tetraploid complementation assays (indicating that they are capable of differentiating into these tissues to a limited extent), the failure of stem cells to produce the embryo entirely on their own (including all of the “extraembryonic” organs) indicates that stem cells are not totipotent in either sense, but rather are merely pluripotent, producing only part of the whole embryo in the context of an embryonic process that they do not independently initiate.

In order to distinguish cells capable to produce all tissue and “extraembryonic layers”, Condic proposes to use term “plenipotent” –

An isolated cell that is able to produce all or most of the derivatives of the ICM and some or all of the TE- and PE-derived cells, but is unable to organize these cells into an integrated body plan.

The ability of ESC and iPS cells to possess more then just pluripotency (but be plenipotent) is a matter of ongoing debate. Some studies showed that ESC are capable to produce spontaneously trophectoderm (ex. placenta) and other “extraembryonic derivatives”, but other studies argue against. Interestingly, very recent study, demonstrated that adult mice could be derived fully (not chimeric) from inner cell mass-derived ESC. One more for plenipotency!

To summarize – totipotency is not:

  • just an ability to produce extraembryonic membranes together with embryonic tissues;
  • just participation in development (it originates);
  • just expression of markers, associated with ESC or zygote;
  • something which look like or behave like an embryo;
  • associated with artificially induced reprogramming.

Finally, the authors discusses some confusions and consequences of inappropriately used terms in literature:

To describe cells that produce all the derivatives of the zygote, yet are not capable of undergoing development (eg, hESCs and embryonal carcinomas), either new terminology, such as “plenipotent,” or a qualified use of “pluripotent” would be preferable to a misleading application of the term “totipotent” to cells that are not organisms.
Inaccurate use of the term “totipotent” by scientists creates unnecessary ethical controversy.
Public concern over producing embryos by reprogramming reflects confusion over totipotency.

This is the best discussion piece that I’ve ever read on the topic! Highly recommend to read!

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