Biological concepts – endoreplication, endocycling,
endomitosis, decidualization, trophoblast, megakaryocyte
Last week we learned that polyploidy plays a role in cancer
development and is the number one cause of spontaneous abortions in humans. Polyploidy
is just no darn good.
 |
There’s
alot to fret about once you hit the
atmosphere.
But take heart, you’ve already found
a
way to make a cancer-like pathway work for you.
Don’t
worry about the details, you’ll get it all in
Biology
class.
|
For example, osteoclasts (osteo = bone, and clast = to break) form from the fusion of two or more
precursor cells. Since each precursor cell has its own nucleus with a 2n set of
chromosomes (n=23 for humans), the fused cell may have 4n, 6n, 8n, or more
chromosomes, in one or more nuclei. New evidence shows that not only can they fuse, but they can also
fission to form more osteoclasts when needed. This had not even been hinted at before.
Osteoclasts eat bone; you are forever tearing down bone and
replacing it with new bone. If you lift weights and build bigger muscles, you
need bigger bones onto which you can attach your now stupendous guns. About
every ten years or so, you have an entirely new skeleton!
Polyploid cells can be formed when diploid cells
fuse, but it is more interesting when they are formed by the processes of endoreplication (endo = within). Normally, most cells just hum along, growing (G1),
then replicating their DNA (S), then growing some more (G2), and finally
dividing into two daughter cells by mitosis
(M). The two new cells then repeat the process. This is called the cell cycle,
and is abbreviated as G1, S, G2, M.
The mitosis portion of the cell cycle itself has several
parts that we all learned in biology class – shout them out with me - prophase,
metaphase, anaphase, and telophase! At the end of telophase, the two daughter
cells finally decide they can’t be roommates any longer, and they divide up
their belongings.
 |
The
phases of mitosis finish up by dividing the cytoplasm and
nucleoplasm. You can see that the cytokinesis starts first,
with
the appearance of the cleavage furrow, but karyokinesis
is
completed before cytokinesis is done. Therefore,
you can’t have
complete cytokinesis with defective or
incomplete karyokinesis.
|
In endoreplication, one or both of these processes is turned
off, so the two daughter cells continue to share a room, but now the room has
twice as much DNA (4n instead of 2n). The cell skips at least a portion of M
phase, and the cell cycle becomes G1, S, G2 ----G1, S, G2, etc. It may occur just once, producing a
tetraploid cell, or it may occur several times, forming huge cells with 32n or
more chromosome sets.
If the cell skips mitosis all together, the process is
called endocyling. In this case, the
chromatids don’t separate in anaphase, and you end up with chromatids that
remain stuck together at their centromeres. If they replicate again in the next
S phase, you end up with an octopus-looking chromosome with several arms sticking
out – called a polytene chromosome.
 |
The left side of the cartoon shows endocycling.
Skipping
mitosis altogether keeps the chromatids
connected
and forms polytene chromosomes.
Endomitosis
is on the right, where the cell goes
through
part of mitosis, then skips the part where
the
two cells separate, either by skipping
cytokinesis
alone or karyokinesis and cytokinesis.
|
On the other hand, if a cell starts through mitosis and
separates its chromatids, AND THEN decides to not divide, this is called endomitosis. Cells that have undergone
endomitosis have many sets of chromosomes. Endomitosis without cytokinesis
results in large cells with multiple diploid nuclei because karyokinesis
separated the nuclei. Endomitosis without karyokinesis and cytokinesis results
in large cells with a single polyploid nucleus. You can see that polyploidy would
need to be highly regulated to keep it from getting out of control.
So how is that polypoloidy is crucial for our survival? It
turns out that that some specialized cells of the embryo undergo
polyploidization as the embryo implants into the wall of the uterus.
The embryo has an outer layer of cells called the trophoblast; these cells become the
placenta, attach the embryo to the uterine wall, and create the blood vessel connection
between mama and junior. The trophoblast is the first set of cells to
differentiate in the embryo and they become several different types of trophoblasts.
One type in particular, the extravillous cytotrophoblasts (ECTs), spread out from the
developing placenta and burrow into the uterine wall. This creates the tight
attachment between mom and embryo. The ECTs also send out hormones to rearrange
the mother’s blood vessels, forming the umbilical cord and vessels. This is how
the growing baby gets all its nourishment until delivery.
ECTs have been studied most in rodents; they weren’t
recognized in humans until just recently. However, a late 2012 study has shown that ECTs are
released from the placenta and can be studied by collecting them at the cervix.
The cells were sufficient to determine the sex of the child after only 5 weeks
of gestation, and were generally of 4n-8n ploidy. Interestingly, female fetuses
tended to form ECTs at a rate almost 7x higher than male fetuses – you’re guess
is as good as mine as to why that might be.
 |
In
panel A there is a bunch of abbreviations. VT is the villous
trophoblasts
that make the connection to the decidua (DD).
In
the black box which is enlarged in panel B, you can see the
extravillous
cytotrophoblast (EVT here) cells invading the
decidua. Both the EVT and the decidua are polyploid.
|
The reason that cells of the decidua must be polyploid is
unknown, but the fact that polyploidization begins at the point of implantation
and spreads to a greater part of the uterus tells you that they are necessary. A new study points to a few possible reasons. Comparing polyploid decidua to non-polyploid decidua showed
that many genes were up-regulated or down-regulated.
The up-regulated genes had to do with metabolism, especially
the mitochondrial energy production. On the other hand, down-regulated genes
had to do with apopotosis and immune function. These results suggest that
polyploidization of the decidua is meant to increase cell functions for the
benefit of the embryo, and this takes energy (so more mitochondrial function),
while at the same time making sure the cells survive to support the fetus until
delivery (reduced apoptosis gene function) and protection of the fetus from the
mother’s immune system (the baby is a foreign body after all).
So baby has polyploid cells that mediate joining with the
mother, and mom has polyploid cells that also work in the formation of the
link between the two. Everyone has to bring polyploidy to the party, or ain’t
nobody getting born!
However, polyploidy in fetal development is only part of the
story. You don’t abandon polyploid cells altogether once you are born or give
birth. All of us have polyploid cells in our bodies right now. Take megakaryocytes for instance.
When you cut yourself, or there is a leak in a blood vessel,
platelets arrive to help close the hole and stop the bleeding. Platelets are of
irregular shape and are sticky, so they tend to get stuck along the edges of
broken blood vessels. Then other things stick to them, a few dozen enzymatic
reactions take place with myriad proteins, you form a clot (called a thrombus in the medical world).
 |
I
have described how platelets are important for coagulation.
This
cartoon shows a break in the cell on the bottom, and
ALL
THE STUFF that has to happen to forma thrombus (clot).
Platelets
are central, but they are certainly not all the story.
|
Hepatocytes
(liver cells), smooth muscle cells in blood vessels, heart muscle cells – these
can all be polyploid. In hepatocytes, polyploidization occurs in cells that are
done dividing and specializing (terminally differentiated) and are now just doing
their job. Fetal and newborn liver cells are exclusively diploid, but 30-40% of
adult hepatocytes are polyploid.
Polyploidy may be a way to increase liver metabolism and
function without going through cell division. Or it may help to protect the
cell from the effects of individual mutations. Since the liver is involved in
breaking down toxins, it’s a good guess that some genes will mutate. Having
extra copies around would prevent a mutation from inhibiting cell function. One mutated gene can be compensated for by an additional normal gene.
On the other hand, smooth muscle cells seem to undergo
polyploidization as a prerequisite to senescence; they are aged and they just
stop working. This interesting, since we said last week that cancer cells are more likely escape therapy induced senescence by becoming polyploid. Once again, biology
can turn the ordinary on its head.
We have discussed the appearance of a polyploid mammal and
crucial sets of polyploid cells in humans. These are the exceptions in higher
vertebrates. But in other organisms, polyploidy is a key to evolution. Next
time we’ll talk about the exceptional role of polyploidy in the development of plants.
For
more information or classroom activities, see:
Osteoclasts
and bone remodeling –
Endoreplication
–
http://www.news-medical.net/news/20111031/Researchers-shed-light-on-inner-workings-of-endocycle.aspx
Trophoblast
and decidualization–
Megakaryocytes
–
No comments:
Post a Comment