Stem Cells Use 'First Aid Kits' to Repair Damage

Stem Cells Use 'First Aid Kits' to Repair Damage

Thursday, 18 September 2014

Stem cells hold great promise as a means of repairing cells in conditions such as multiple sclerosis, stroke or injuries of the spinal cord because they have the ability to develop into almost any cell type. Now, new research shows that stem cell therapy can also work through a mechanism other than cell replacement.

Confocal super resolution imaging of the rapid

(2h) up-take of CD63-RFP EVs packed via

target cell fEGFP (green) plasma membrane in

vitro. Credit: Design and artwork by CongJian

Zhao.

In a study published today in Molecular Cell, a team of researchers led by the University of Cambridge has shown that stem cells "communicate" with cells by transferring molecules via fluid filled bags called vesicles, helping other cells to modify the damaging immune response around them.

Although scientists have speculated that stem cells might act rather like drugs – in sensing signals, moving to specific areas of the body and executing complex reactions – this is the first time that a molecular mechanism for this process has been demonstrated. By understanding this process better, researchers can identify ways of maximising the efficiency of stem-cell-based therapies.

Dr Stefano Pluchino from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, who led the study, said:

"These tiny vesicles in stem cells contain molecules like proteins and nucleic acids that stimulate the target cells and help them to survive – they act like mini "first aid kits".

"Essentially, they mirror how the stem cells respond to an inflammatory environment like that seen during complex neural injuries and diseases, and they pass this ability on to the target cells. We think this helps injured brain cells to repair themselves."

Mice with damage to brain cells – such as the damage seen in multiple sclerosis – show a remarkable level of recovery when neural stem/precursor cells (NPCs) are injected into their circulatory system. It has been suggested that this happens because the NPCs discharge molecules that regulate the immune system and that ultimately reduce tissue damage or enhance tissue repair.

The team of researchers from the UK, Australia, Italy, China and Spain has now shown that NPCs make vesicles when they are in the vicinity of an immune response, and especially in response to a small protein, or cytokine, called Interferon-gamma which is released by immune cells. This protein has the ability to regulate both the immune responses and intrinsic brain repair programmes and can alter the function of cells by regulating the activity of scores of genes.

Their results show that a highly specific pathway of gene activation is triggered in NPCs by IFN-gamma, and that this protein also binds to a receptor on the surface of vesicles. When the vesicles are released by the NPCs, they adhere and are taken up by target cells. Not only does the target cell receive proteins and nucleic acids that can help them self-repair, but it also receives the IFN-gamma on the surface of the vesicles, which activates genes within the target cells.

The researchers, who were funded by the European Research Council and the Italian MS Society, used electron microscopy and super resolution imaging to visualise the vesicles moving between the NPCs and target cells in vitro.

"Our work highlights a surprising novel role for stem-cell-derived vesicles in propagating responses to the environment," added Pluchino.

"It represents a significant advance in understanding the many levels of interaction between stem cells and the immune system, and a new molecular mechanism to explain how stem-cell therapy works."

Source: University of Cambridge

Contact: Louise Walsh

Reference:

Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells

Chiara Cossetti, Nunzio Iraci, Tim R. Mercer, Tommaso Leonardi, Emanuele Alpi, Denise Drago, Clara Alfaro-Cervello, Harpreet K. Saini, Matthew P. Davis, Julia Schaeffer, Beatriz Vega, Matilde Stefanini, CongJian Zhao, Werner Muller, Jose Manuel Garcia-Verdugo, Suresh Mathivanan, Angela Bachi, Anton J. Enright, John S. Mattick, Stefano Pluchino

Molecular Cell, September 18, 2014, DOI: http://dx.doi.org/10.1016/j.molcel.2014.08.020

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Self-digestion as a Means of Survival

How cells recognize and deal with protein waste Saturday, 28 February 2009 In times of starvation, cells tighten their belts: they start to digest their own proteins and cellular organs. The process - known as autophagy - takes place in special organelles called autophagosomes. It is a strategy that simple yeast cells have developed as a means of survival when times get tough, and in the course of evolution, it has become a kind of self-cleaning process. In mammalian cells, autophagosomes are also responsible for getting rid of misfolded proteins, damaged organelles or disease-causing bacteria. If this process malfunctions, it can result in infectious diseases, as well as cancer, Parkinson's or Alzheimer's disease. Biochemists at Frankfurt's Goethe University, working together with scientists from the University of Tromsø in Norway, the Weizmann Institute in Israel and the Tokyo Metropolitan Institute in Japan have just come up with an explanation as to how autophagosomes know exactly which proteins and organelles they should degrade. "Although autophagy has been known for more than 30 years, it is astonishing that no-one thought of looking for the receptors that make this process so selective" explains Prof. Ivan Dikic from the Institute of Biochemistry II and the Cluster of Excellence 'Macromolecular Complexes' in Frankfurt. He had a head start in this field, since over several years, he and his group have researched and now published their work on another self-cleaning process in the cell: the degradation of small proteins in the proteasome, which acts as a kind of molecular shredder. "We know that the molecules which are destined to be discarded are marked with the small protein ubiquitin and this is recognised by a receptor located at the gateway to the proteasome. It was natural to suggest a similar recognition mechanism for protein degradation by autophagosomes", says Dikic. Unlike the proteasome, which is a complex molecular machine, autophagosomes simply consist of a double membrane that floats around in the cytoplasm. Not unlike white blood cells, they can engulf larger proteins or even whole cell organelles. But since they have no enzymes with which they can digest their own cargo, they fuse with lysosomes. When a Yoshinori Ohsumi's group in Japan reported that they had discovered ubiquitin-like proteins (ATG8) on the outer surface of the autophagosome and gone on to prove that they were specific for autophagy, Dikic and his colleague Dr. Vladimir Kirkin immediately began their search for potential autophagy receptors that might bind to the family of ATG8 proteins. The team of international scientists report in the current issue of the renowned journal "Molecular Cell", that by employing methods from cell biology, biochemistry and mouse genetics, they have been able to identify a further protein, in addition to the known p62/SQSTM1 protein, that may act as a receptor. This is the protein NBR1, which has long been associated with cancer. Both proteins have a similar chain-like structure. At one end, they bind to the ubiquitin that marks the protein aggregates and organelles that are to be degraded. Next to the ubiquitin-binding site is a domain that binds to the ATG8 proteins found at the autophagosomal membrane. Here, the protein waste can dock onto the autophagosome and can then be wrapped up in the membrane. Vladimir Kirkin, who is now at Merck Serono in Darmstadt, is continuing these investigations with the long-term aim of developing new drugs. Dikic and his group are now concentrating on mitochondria - which are implicated in oxidative stress in cells - hoping to locate the receptors for autophagy on these important organelles. Reference: A Role for NBR1 in Autophagosomal Degradation of Ubiquitinated Substrates Vladimir Kirkin, Trond Lamark, Yu-Shin Sou, Geir Bjorkoy, Jennifer L. Nunn, Jack-Ansgar Bruun, Elena Shvets, David G. McEwan, Terje H. Clausen, Philipp Wild, Ivana Bilusic, Jean-Philippe Theurillat, Aud Overvatn, Tetsuro Ishii, Zvulun Elazar, Masaaki Komatsu,I van Dikic and Terje Johansen Molecular Cell, Volume 33, Issue 4, 505-516, 27 February 2009, doi:10.1016/j.molcel.2009.01.020 ......... ZenMaster

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