Stem cell signaling: Molecular morse code in stem cells encrypting differentiation information

Date:
February 24, 2022
Source:
Max Planck Institute of Molecular Physiology
Summary:
Divide, differentiate or die? Making decisions at the right time
and place is what defines a cell's behavior and is particularly
critical for stem cells of an developing organisms. Decision
making relies on how information is processed by networks of
signaling proteins. Scientists have now revealed that ERK, a
key player in stem cell signaling, processes information through
fast activity pulses. The duration of the pulsing interval, might
encode information essential for divergent fate decision in stem
cell cultures.



FULL STORY ========================================================================== Divide, differentiate or die? Making decisions at the right time and
place is what defines a cell's behavior and is particularly critical
for stem cells of an developing organisms. Decision making relies on
how information is processed by networks of signaling proteins. The
teams around Christian Schro"ter from the Max Planck Institute of
Molecular Physiology in Dortmund and Luis Morelli from the Instituto de Investigacion en Biomedicina de Buenos Aires (IBioBa) have now revealed
for the first time, that ERK, a key player in stem cell signaling
processes information through fast activity pulses. The duration of the
pulsing interval, might encode information essential for divergent fate decision in stem cell cultures.


========================================================================== During their development into the later embryo, stem cells go through
a series of developmental steps. The transition between those steps
is controlled by signaling molecules that are exchanged between
neighboring cells. One of the most critical signals during early
mammalian embryogenesis is the fibroblast growth factor 4 (FGF4). When
it is recognized by a cell, this information is processed by a network
of signaling proteins, resulting in a cellular response.

The key players of the network, their role and interactions are by
now well known, however only little is known about the signaling
dynamics. But what does dynamics actually mean, and why are dynamics
important? Dynamics determine cell fate In the posterchild example
for the importance of dynamics in signal transduction, two different
molecular signals trigger different cellular responses -- differentiation
and cell growth -- even though they use the same signal transduction
network. This is possible because the dynamics with which the signal transduction system is activated are specific for each of the two
molecular signals: Whereas one activates the system for a short time
leading to cell growth, the other activates the same system for a long
time resulting in differentiation. Thus, signaling dynamics are clearly important to determine a cell's fate. However, many studies so far could
only look at fairly slow dynamics that unfolded over hours and that were
the same in all cells; they were blind to fast dynamics, especially if
these were different between stem cells in the same dish.

ERK activity pulses every six to seven minutes The teams around Christian Schro"ter and Luis Morelli were now able to gain a better understanding
of the fast signaling dynamics in stem cells. By introducing a fluorescent sensor in living stem cells, the scientists could measure the activity of
the major signaling protein ERK in real-time. ERK activity is important
for translating molecular signals into a genetic response and thus
for regulating stem cell differentiation. "Measuring ERK activity in
single stem cells at short timescale is experimentally very demanding
and was never done in such a way before. For the first time, we could
observe, that ERK activity pulses every six to seven minutes, faster
than similar signals previously shown in other cell systems. In single
cells, the pulses occurred often very regularly one after the other,
but pulsing patterns were strikingly different between individual cells," Christian Schro"ter says. The researchers could also observe, that with increasing FGF4 signal, the number of pulses increases when summing
up over many cells, even though the durations of single pulses did not
change with FGF4.

Interdisciplinary approach -- Intercontinental collaboration "This kind
of data and its role on cell signaling is very hard to interpret.

And that is the point, where our expertise kicked in," Luis Morelli
says, longstanding collaboration partner and group leader at the IbioBa,
a partner Institute of the Max Planck Society. "We had to develop a new theoretical approach to describe the dynamics in time series. By doing
this, we saw that the duration of the pulsing interval might encode information, since we could find pulses and silence. We call this new
dynamic feature intermittent oscillations ." "Oscillations are a more
and more recognized feature of signaling processes. We hypothesize that
the intermittent oscillations we found in stem cells work like a kind
of morse code that encodes differentiation information. Presumably, it
is the switch from pulsing to silence that plays a decisive role. The
question is now, what do the dynamics tell us about the organization of signaling in stem cells? How are cells able to read the oscillations,
and how do they affect the cell's behavior? I am convinced that close collaboration between experimentalists and theorists is required to
unravel the origins and functions of this new dimension in stem cell
biology one day," Christian Schro"ter says.

========================================================================== Story Source: Materials provided by Max_Planck_Institute_of_Molecular_Physiology. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Dhruv Raina, Fiorella Fabris, Luis G. Morelli, Christian Schro"ter.

Intermittent ERK oscillations downstream of FGF in mouse embryonic
stem cells. Development, 2022; 149 (4) DOI: 10.1242/dev.199710 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220224140839.htm

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