Developmental Biology - Cell Plasticity|
A New Method to Regulate Cell Plasticity
Plasticity is essential to the developing embryo, the function of our immune system, and is crucial in cancer...
Having "plasticity" is a property that allows a cell to take on different as well as reversible identities. Plasticity is essential in embryo development and in the function of our immune system. It is also crucial in cancer as many cancer cells use "plasticity" to become resistant to chemotherapy and thus invade and colonise distant parts of the body.
Headed by the Catalan Institution for Research and Advanced Studies (ICREA), researcher Manuel Serrano along with scientists at the Cellular Plasticity and Disease Laboratory at the Institute for Research in Biomedicine (IRB, Barcelona) have discovered a way to regulate this property by "blocking plasticized or flexibility" in cells. The work appears in Experimental Cell Research.
"The identity of each cell type is defined by a unique gene expression program.
What makes plastic cells special is how they can make genes function at low levels to display other attributes in addition to their original gene identity.
This "background noise" is what allows cell components to change identity at any given time. What had, at one moment, been "background noise" now becomes the dominant genetic program.
Regulating Gene Expression to Modify Plasticity
Until now, methods used to block cell plasticity were based on inhibiting some of the external stimuli that cells receive. But these approaches usually interfere with cell multiplication and can damage cells.
The new method developed by Serrano's lab, which is supported by The "Caixa" Foundation, focuses on a profound mechanism regulating gene expression. It does not affect cell viability and is completely reversible. Key to this new approach is inhibition of the protein CDK8.
"We observed inhibiting CDK8 strengthens the expression/function of genes determining cell identity. But, at the expense of switching off the "background noise" of alternative identities. Cells become fixed in a specific identity, losing plasticity."
Cian J Lynch postdoctoral fellow and first author.
Important Implications in Biomedicine
The capacity to regulate cell plasticity has many advantages in biomedical research. It allows study of all cellular processes in which plasticity is a key element, such as cancer and embryo development. The present study focused on embryonic stem cells. Their great plasticity makes them highly attractive for cell therapy applications. However, this same plasticity is a real challenge when culturing stem cells in the lab.
"Because of the intrinsic plasticity of embryonic stem cells, cultures produced in the lab are highly heterogeneous, and previous methods available to reduce plasticity were very harmful to the cells. This was a practical problem with no apparent solution."
Raquel Bernad PhD, post doctural fellow. and co-author of the study.
Researchers demonstrated it is possible to culture embryonic stem cells in the presence of a CDK8 inhibitor. This makes the cultured cells less plastic, more homogeneous, yet does not damage cells. Something not achieved until now. Simply removing the inhibitor CDK8, restores plasticity back to the cells.
Furthermore, scientists from other laboratories have observed that this new method may have implications in autoimmune diseases in which the plasticity of T cells make them adopt an overly active state, leading to an exacerbated immune response.
"Cell plasticity is known to be a key factor underlying resistance to chemotherapy. By blocking cell plasticity, we hope to improve reactions to chemotherapy by achieving more homogeneous and lasting responses."
Human na´ve pluripotent stem cells (PSCs) represent an optimal homogenous starting point for molecular interventions
and differentiation strategies. This is in contrast to the standard primed PSCs which fuctuate in
identity and are transcriptionally heterogeneous. However, despite many efforts, the maintenance and expansion
of human na´ve PSCs remains a challenge. Here, we discuss our recent strategy for the stabilization of human PSC
in the na´ve state based on the use of a single chemical inhibitor of the related kinases CDK8 and CDK19. These
kinases phosphorylate and negatively regulate the multiprotein Mediator complex, which is critical for enhancerdriven
recruitment of RNA Pol II. The net effect of CDK8/19 inhibition is a global stimulation of enhancers,
which in turn reinforces transcriptional programs including those related to cellular identity. In the case of
pluripotent cells, the presence of CDK8/19i effciently stabilizes the na´ve state. Importantly, in contrast to
previous chemical methods to induced the na´ve state based on the inhibition of the FGF-MEK-ERK pathway,
CDK8/19i-na´ve human PSCs are chromosomally stable and retain developmental potential after long-term
expansion. We suggest this could be related to the fact that CD.
Cian J. Lynch, Raquel Bernad, Isabel Calvo and Manuel Serrano.
This study has been possible thanks to the collaboration of national and international centres such as the Centro Nacional de Investigaciones Oncolˇgicas (CNIO) in Madrid, the University of Cambridge in the UK, the University of Aveiro in Portugal, the Institute for Bioengineering of Catalonia (IBEC) in Barcelona, the Institut Curie, University of Lyon and the Institute for Molecular Genetics of Montpelier in France, the University of Oviedo and the Spanish CIBER-BBN.
The study was supported by "la Caixa" Foundation and received funding by the European Research Council (ERC)and the Plan Nacional of the Spanish Ministry of Science and Innovation.
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Sep 29 2020 Fetal Timeline Maternal Timeline News
Researchers took a chemical approach and inhibited CDK8 kinase to stabilize pluripotent cells. Pictured is a mouse blastocyst with its three cell types: Trophoblasts (PURPLE), Primitive Endoderm cells (RED), and Na´ve Pluripotent cells (GREEN). CREDIT Cian J. Lynch, IRB, Barcelona, Spain.