<p>During gestation, the maternal
liver undergoes various adaptive changes to cope with the increasing
physiological and metabolic demands from both maternal and fetal compartments.
Among these changes are robust growth and changes in transcriptome profile.
However, how these events happen, and other aspects of this physiological
phenomenon remains unexplored. Therefore, we aimed at further understanding how
maternal liver responds to pregnancy. We used BrdU labeling combined with a
virus-based tracing approach to quantify the percentage of maternal hepatocytes
undergoing DNA synthesis and division over the course of gestation in mice. </p>
<p>We found that ~50% maternal
hepatocytes entered S-phase but, unexpectedly, did not undergo cytokinesis.
This strongly suggests that maternal hepatocytes in fact undergo
endoreplication instead of hyperplasia, as believed previously. Pericentral
Axin2<sup>+</sup> hepatocytes were reported to behave as liver stem cells
responsible for liver homeostasis and turnover. We generated an <i>in vivo</i> fate-tracing mouse model to
monitor the behavior of these cells in the maternal liver. Our results showed
that they did not proliferate during pregnancy, homeostasis, and following
partial hepatectomy. Curiously, we uncovered that, hepatocytes exhibit
developmental phenotypes at mRNA level pre-pregnancy and at both mRNA and
protein level during pregnancy. In the non-pregnant state, hepatocytes reserved
mRNA expression of liver progenitor marker genes <i>Cd133</i> and <i>Afp</i>, which are localized
in the nuclei, without protein translation. During gestation, maternal
hepatocytes displayed cytoplasmic translocation of <i>Cd133</i> and <i>Afp</i>
transcripts, concomitant with corresponding protein expression. </p>
<p>Overall, all maternal hepatocytes became CD133<sup>+</sup>,
and a subset of them express AFP. Additionally, in non-pregnant livers, mRNA of
<i>Epcam</i>, another liver progenitor
marker, was expressed within majority of hepatocytes, whereas its protein was
solely translated in the pericentral region. In contrast, by end-gestation, EPCAM
protein expression switched to the periportal region. These observations
indicate that maternal hepatocytes exhibit heterogeneous developmental
phenotypes, partially resembling fetal hepatocytes. It is intriguing why mature
hepatocytes dedifferentiate into a progenitor state in response to pregnancy.
AFP is considered to be produced primarily from fetal liver and thus is used to
evaluate fetal development health. </p>
A potential clinical
relevance of our data is that we identified maternal liver as a new source of
AFP. The hippo signaling pathway has been shown to potently control liver
growth and hepatocyte heterogenicity. Surprisingly, we found that pregnancy neither
altered the expression nor activities of the components of this pathway and its
effector YAP1/TAZ. This finding indicates that pregnancy-induced maternal liver
growth is not driven by hippo-YAP1 pathway. However, we demonstrate that the
presence of YAP1 is essential for CD133 protein expression in maternal
hepatocytes. Collectively, we revealed that, as pregnancy advances, maternal
hepatocytes likely undergo endoreplication and display developmental
phenotypes. Mechanistically, YAP1 dictates the expression of CD133, contributing
to the pregnancy-dependent phenotypic changes of maternal hepatocytes.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/15044022 |
| Date | 06 August 2021 |
| Creators | Shashank Manohar Nambiar (11177052) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/Maternal_Hepatic_Adaptations_to_Pregnancy/15044022 |
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