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Eric Erkenbrack @Erky321
, 21 tweets, 8 min read Read on Twitter
Today, our paper

“The mammalian decidual cell evolved from a cellular stress response”

is published @PLOSBiology…

👇👇 Here’s a thread for a broader audience w/ highlights of the data/figures

a kind of Twitter paper summary (TPS Report)

The idea for this project was conceived by Günter Wagner at @yale_eeb @YaleWestCampus

Together we designed, analyzed, & executed the experiments with co-authors Jamie Maziarz, @OliGriffith, @CongLiang3, @ArunRChavan, & @mnnamani
Here’s a summary: in the recent common ancestor of mammals, 👶 attaching to mom’s uterus caused inflammation & cell stress. Ancestrally mom just wanted 👶 out! In the lineage leading to🏃‍♀️, this stress response became a structural part of a novel cell type, the decidual cell
Let’s break down the title first

‘The mammalian decidual cell’
is a specialized cell in the uterus of many mammals including 🏃‍♀️

Decidual cells function in reproduction, are shed or absorbed during menstruation, & help 👶 attach to mom thru the placenta during pregnancy
‘cellular stress response’

Cells get stressed too! Dividing, metabolizing (eg ethanol), doing cell stuff-it’s not easy. Cells deal w/ stress by turning on/off groups of genes (pathways) for each stressor. Evolutionarily these responses are very old & thus very similar in animals
The decidual cell is specific to a large group of mammals (eutherians). By comparing human decidual cells w/ related cells in mammals w/ different 🤰we can find out what changed to give rise to it. It’s an opportunity to understand how a new thing (cell type) arose in evolution
DYK: studying🤰in mammals helps us understand not only human🤰but also informs us about evolution? Many aspects of🤰vary, eg an 🐘 is pregnant for 2 years! Length of🤰& how 👶 attaches to mom are just a few varying aspects. Studying this variation aids in understanding evolution
Decidual cells (DSC) in humans and other placental mammals arise from precursor cells in the uterus called ESF cells, which are transformed into DSC by hormones during pregnancy & the menstrual cycle. We treat ESF w/ hormones in lab to turn them into DSC.
We isolated ESF from the uterus of a distantly related mammal, the marsupial opossum Monodelphis domestica, which goes thru🤰in a way we think is close to how the recent common ancestor of these mammals went thru🤰

We call these cells MdESF

A M domestica w/ so many babies gif!!
MdESF are related to human ESF & DSC. They share functional features & an evolutionary history. Because of this, we say they share a molecular ‘identity’, and we want to know what that is. Hormone treatment causes HsESF to become HsDSC. Experiment: Treat MdESF w/ the hormones
For this experiment we were particularly interested in two different sets of genes: regulatory genes, ie genes that control the production of other genes, & differentiation genes, ie genes/proteins that are functionally important for the processes that make a DSC a DSC
When treated w/ DSC hormones, MdESF increased the levels of core DSC regulatory genes (B) but not DSC differentiation genes (C), telling us part of DSC identity is there, but another part is missing. Under the 🔬 (D,E) the cells were telling us something as well: we’re stressed!
Ok so which genes to look at?

In species as different as hydra (the incredible maybe immortal 🌊 creature!) and 🏃‍♀️, one family of genes that is known to be critical for cellular stress response is the forkhead 📦 class O genes, so called FOXO 🦊 family
In human, FOXO1 is known to control regulation of important DSC differentiation genes. We can see how 🦊O1 behaves in the cell by attaching an antibody to it. Normally the protein is not present. When you treat w/ hormones, it (red) becomes visible in the cell (nucleus is blue)
In MdESF treated w/ hormones, we saw a very similar response, suggesting that the behavior (regulation) of 🦊 FOXO1 protein is similar in opossum ESF and human ESF (G in image). We also see this protein respond specifically to oxygen radicals (F), suggesting it responds to stress
We asked what 🦊 FOXO1 is doing if not controlling the production of differentiation genes as in HsDSC.

We reduced (by siRNA) its level in MdESF & treated w/ hormones. The graphs show ‘blobs’, which are thousands of cells, getting bigger when treated, indicating cell💀& stress
Interestingly, it was already known that stress genes, including stressors like free radicals, were important to DSC differentiation. This was puzzling 🤔. However, when viewed in light of our results and the evolution of pregnancy itself, it becomes more clear why this may be
We proposed that, in the lineage leading to eutherians &🏃‍♀️, stress pathways became a critical part of DSC identity as 👶 became more invasive in mom’s uterus. This allowed mom’s uterus to cope w/ cell stress as it became more advantageous to keep 👶 inside mom for longer ⏱
Particular types of cells are related in evolution similar to how species are related, a process called cell type evolution. Each generation iterations of cell types arise as the body develops. As species diverge, the molecular characteristics & functions of cell types can change
Here we aimed to shed💡on how a novel cell type arose during mammal evolution. We showed that distantly related cells in uteri of mammals have similar identity but respond in species specific ways due to their evolutionary history.

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