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February 2020

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Scientists discover how rogue communications between cells lead to leukemia — ScienceDaily

New research has deciphered how rogue communications in blood stem cells can cause Leukemia.

The discovery could pave the way for new, targeted medical treatments that block this process.

Blood cancers like leukemia occur when mutations in stem cells cause them to produce too many blood cells.

An international team of scientists, including researchers at the University of York, have discovered how these mutations allow cells to deviate from their normal method of communicating with each other, prompting the development of blood cells to spiral out of control.

The scientists used super-resolution fluorescent microscopy to study the way blood stem cells talk to each other in real time.

They observed how cells receive instructions from ‘signalling proteins’, which bind to a receptor on the surface of another cell before transmitting a signal telling the cell how to behave.

Blood stem cells communicate via cytokines, which are one of the largest and most diverse families of signalling proteins and are critical for the development of blood cells and the immune system.

Understanding this process led researchers to the discovery that mutations associated with certain types of blood cancers can cause blood stem cells to ‘go rogue’ and communicate without cytokines.

The stem cells begin to transmit uncontrolled signals causing the normal system of blood cell development to become overrun, producing an imbalance of healthy white and red blood cells and platelets.

Professor Ian Hitchcock from the York Biomedical Research Institute and the Department of Biology at the University of York, said: “Our bodies produce billions of blood cells every day via a process of cells signalling between each other. Cytokines act like a factory supervisor, tightly regulating this process and controlling the development and proliferation of the different blood cell types.

“Our observations led us to a previously unknown mechanism for how individual mutations trigger blood stem cells to start signalling independently of cytokines, causing the normal system to become out of control and leading to diseases like leukemia.

“Understanding this mechanism may enable the identification of targets for the development of new drugs.”

This research team used a combination of molecular modelling, structural biology, biophysics, super-resolution microscopy and cell biology to demonstrate for the first time that these specific receptors on the surface of blood stem cells are linked by cytokines to form pairs.

Co-author of the study, Professor Jacob Piehler from Osnabrück University, said: “By directly visualising individual receptors at physiological conditions under the microscope, we were able to resolve a controversy that has preoccupied the field for more than 20 years.”

Professor Ilpo Vattulainen from the University of Helsinki, added: “Our biomolecular simulations unveiled surprising features concerning the orientation of active receptor pairs at the plasma membrane, explaining how mutations render activation possible without a ligand (such as a cytokine). These predictions were subsequently confirmed experimentally”

First author Dr. Stephan Wilmes, who started the project as a Postdoc at Osnabrück University before moving to the University of Dundee: “It was truly inspiring to tackle this highly relevant biomedical question by applying cutting-edge biophysical techniques. Here in Dundee, I had the chance to perform complementary activity assays, which corroborated our mechanistic model.”

The study is published in the journal Science and was carried out in collaboration between the universities of York, Dundee, Osnabruck (Germany), Helsinski (Finland), Stanford and New York (USA).

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Materials provided by University of York. Note: Content may be edited for style and length.

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Computer simulations visualize how DNA converts cells into stem cells — ScienceDaily

Researchers of the Hubrecht Institute (KNAW — The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells. Their findings are published in the Biophysical Journal.

A cell’s identity is driven by which DNA is “read” or “not read” at any point in time. Signalling in the cell to start or stop reading DNA happens through proteins called transcription factors. Identity changes happen naturally during development as cells transition from an undesignated cell to a specific cell type. As it turns out, these transitions can also be reversed. In 2012, Japanese researchers were awarded the Nobel prize for being the first to push a regular skin cell backwards to a stem cell.

A fuller understanding of molecular processes towards stem cell therapies

Until now, it is unknown how the conversion of a skin cell into a stem cell happens exactly, on a molecular scale. “Fully understanding the processes with atomic details is essential if we want to produce such cells for individual patients in the future in a reliable and efficient manner,” says research leader Vlad Cojocaru of the Hubrecht Institute. “It is believed that such engineered cell types may in the future be part of the solution to diseases like Alzheimer’s and Parkinson’s, but the production process would have to become more efficient and predictable.”

Pioneer transcription factor

One of the main proteins involved in the stem cell generation is a transcription factor called Oct4. It induces gene expression, or activity, of the proteins that ‘reset’ the adult cell into a stem cell. Those genes induced are inactive in the adult cells and reside in tightly packed, closed states of chromatin, the structure that stores the DNA in the cell nucleus. Oct4 contributes to the opening of chromatin to allow for the expression of the genes. For this, Oct4 is known as a pioneer transcription factor.

The data from Cojocaru and his PhD candidate — and first author of the publication — Jan Huertas show how Oct4 binds to DNA on the so-called nucleosomes, the repetitive nuclear structures in chromatin. Cojocaru: “We modelled Oct4 in different configurations. The molecule consists of two domains, only one of which is able to bind to a specific DNA sequence on the nucleosome in this phase of the process. With our simulations, we discovered which of those configurations are stable and how the dynamics of nucleosomes influence Oct4 binding. The models were validated by experiments performed by our colleagues Caitlin MacCarthy and Hans Schöler in Münster.”

One step closer to engineered factors

This is the first time computer simulations show how a pioneer transcription factor binds to nucleosomes to open chromatin and regulate gene expression. “Our computational approach for obtaining the Oct4 models can also be used to screen other transcription factors and to find out how they bind to nucleosomes,” Cojocaru says.

Moreover, Cojocaru wants to refine the current Oct4 models to propose a final structure for the Oct4-nucleosome complex. “For already almost 15 years now, we know that Oct4 together with three other pioneer factors transforms adult cells into stem cells. However, we still do not know how they go about. Experimental structure determination for such a system is very costly and time consuming. We aim to obtain one final model for the binding of Oct4 to the nucleosome by combining computer simulations with different lab experiments. Hopefully, our final model will give us the opportunity to engineer pioneer transcription factors for efficient and reliable production of stem cells and other cells needed in regenerative medicine.”

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Materials provided by Hubrecht Institute. Note: Content may be edited for style and length.

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