Stem cell secrets allow researchers to revamp reprogramming
Researchers have identified factors required to generate nai"ve stem
cells by reprogramming
Date:
March 25, 2022
Source:
Babraham Institute
Summary:
Researchers have identified key factors that promote the
reprogramming of human stem cells to the nai"ve state, which can
be used to model the earliest stages of development. This new
knowledge will help researchers to generate nai"ve pluripotent
stem cells more efficiently and quickly.
Their findings also provide new insights into the mechanisms
that destabilise and reconfigure cell identity during cell state
transitions.
FULL STORY ========================================================================== Researchers from the Babraham Institute's Epigenetics research programme
have been able to learn more about nai"ve stem cell reprogramming
following a genome wide functional screen. Their research, published today
in Science Advances, describes the critical regulators of reprogramming
and offers opportunities for a more efficient, faster way to generate
human nai"ve pluripotent stem cells.
========================================================================== Human pluripotent stem cells (PSCs) are a useful tool for researchers investigating how cells specialise to make every tissue of our body. They
come in two different states, primed and nai"ve. Both types of PSC can self-renew and differentiate into new cell types but they have distinct functions and molecular characteristics.
Group leader Peter Rugg-Gunn explained the importance of these cells:
"Human PSCs in the nai"ve state replicate the key molecular and cellular characteristics of cells in a pre-implantation stage embryo. Importantly,
when nai"ve PSCs are encouraged to self-organise in particular
conditions, they form structures that resemble an early blastocyst stage
of development. By growing these cells in the lab, we can learn about the
key events that happen during human development, and they have potential
uses in personalised medicine. But we need to create high-quality,
stable stem cell populations to be able to conduct our experiments." Pluripotent stem cells are formed either from embryos or using
Nobel Prize- winning methods to remove cell identity from specialised
cells. The majority of reprogramming experiments generate primed PSCs,
which are more developmentally advanced than nai"ve PSCs. Nai"ve PSCs
can be collected directly from human pre-implantation embryos, or more
commonly researchers expose primed PSCs to conditions that induces them to become nai"ve PSCs. Existing methods for reprogramming were inefficient
and slow, preventing researchers' from quickly producing the numbers of high-quality stem cells they needed.
Adam Bendall, PhD student and a lead researcher on the study, said:
"Very little was known about what genetic and epigenetic factors are
required for nai"ve cell reprogramming, and this knowledge gap limited
the design of reprogramming conditions." The low efficiency of nai"ve reprogramming suggests the presence of barriers that limit cells in
reaching the nai"ve state. Adam and his colleagues honed in on these
barriers by performing a large-scale genetic screen to identify genes
that hinder and help reprogramming. They were able to identify a large
number of genes that have a crucial role in nai"ve PSC programming that
had not been previously linked to the process.
The team focused on one epigenetic complex in particular, the PRC1.3
complex, that regulates gene expression without altering the underlying
DNA sequence, and which they found to be essential for the formation of
nai"ve PSCs. Without this complex, the cells undergoing reprogramming
become a completely different type of cell rather than nai"ve PSCs. This suggests that the activity of PRC1.3 could encourage more cells to
reprogram properly, in effect lowering the barrier.
After identifying factors that promote reprogramming, the researchers
also looked at factors that impede reprogramming, exemplified in their
study by an epigenetic protein called HDAC2. Dr Amanda Collier, first
author on the paper, explained: "Excitingly, when we inhibited one of
these factors using selective chemicals, then nai"ve PSC reprogramming
occurred more efficiently and rapidly.
We're able to look at it from both sides; we can remove the barriers and introduce the factors that push cells towards state change." Not only
does this research improve scientists' ability to produce human nai"ve
PSCs, it provides details on the molecular events that occur during the
cell state transition itself, some of which are conserved in developmental regulation in human embryos.
The Rugg-Gunn lab are putting together the pieces of a bigger puzzle
-- the best understanding of the formation and control of nai"ve stem
cells. Their previous research has identified molecular factors that help
to maintain cells in a nai"ve stage. Group leader, Peter Rugg-Gunn said:
"By building up our tools for manipulating pluripotent stem cells, we
can spend more time asking important questions about the pre-implantation embryo. In the longer term, further improvements in working with nai"ve
PSCs might open up the possibility for using these cells in personalised disease models or cell therapies, although this will require more research
on how to differentiate nai"ve PSCs into specialised cell types."
========================================================================== Story Source: Materials provided by Babraham_Institute. Note: Content
may be edited for style and length.
========================================================================== Journal Reference:
1. Amanda J. Collier, Adam Bendall, Charlene Fabian, Andrew A. Malcolm,
Katarzyna Tilgner, Claudia I. Semprich, Katarzyna Wojdyla, Paola
Serena Nisi, Kamal Kishore, Valar Nila Roamio Franklin, Bahar
Mirshekar-Syahkal, Clive D'Santos, Kathrin Plath, Kosuke Yusa,
Peter J. Rugg-Gunn. Genome- wide screening identifies Polycomb
repressive complex 1.3 as an essential regulator of human nai"ve
pluripotent cell reprogramming. Science Advances, 2022; 8 (12)
DOI: 10.1126/sciadv.abk0013 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220325144648.htm
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