Help for a scarred heart: Scarring cells turned to beating muscle

Poets and physicians know that a scarred heart cannot beat the way it used to, but the science of reprogramming cells offers hope–for the physical heart, at least.A team of University of Michigan biomedical engineers has turned cells common in scar tissue into colonies of beating heart cells. Their findings could advance the path toward regenerating tissue that’s been damaged in a heart attack.Previous work in direct reprogramming, jumping straight from a cell type involved in scarring to heart muscle cells, has a low success rate. But Andrew Putnam, an associate professor of biomedical engineering and head of the Cell Signaling in Engineered Tissues Lab, thinks he knows at least one of the missing factors for better reprogramming.”Many reprogramming studies don’t consider the environment that the cells are in — they don’t consider anything other than the genes,” he said. “The environment can dictate the expression of those genes.”To explore how the cells’ surroundings might improve the efficiency of reprogramming, Yen Peng Kong, a post-doctoral researcher in the lab, attempted to turn scarring cells, or fibroblasts, into heart muscle cells while growing them in gels of varying stiffness. He and his colleagues compared a soft commercial gel with medium-stiffness fibrin, made of the proteins that link with platelets to form blood clots, and with high-stiffness collagen, made of structural proteins.The fibroblasts came from mouse embryos. To begin the conversion to heart muscle cells, Kong infected the fibroblasts with a specially designed virus that carried mouse transgenes — genes expressed by stem cells.Fooled into stem cell behavior, the fibroblasts transformed themselves into stem-cell-like progenitor cells. This transition, which would be skipped in direct reprogramming, encouraged the cells to divide and grow into colonies rather than remaining as lone rangers. The tighter community might have helped to ease the next transition, since naturally developing heart muscle cells are also close with their neighbors.After seven days, Kong changed the mixture used to feed the cells, adding a protein that encourages the growth of heart tissue. This helped push the cells toward adopting the heart muscle identity. A few days later, some of the colonies were contracting spontaneously, marking themselves out as heart muscle colonies.The transition was particularly successful in the fibrin and fibrin-collagen mixes, which saw as many as half of the colonies converting to heart muscle.The team has yet to discover exactly what it is about fibrin that makes it better for supporting heart muscle cell. …

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Click chemistry could provide total chemical DNA synthesis, study shows

An interdisciplinary study led by Dr Ali Tavassoli, a Reader in chemical biology at the University of Southampton, has shown for the first time that ‘click chemistry’ can be used to assemble DNA that is functional in human cells, which paves the way for a purely chemical method for gene synthesis.Writing in Angewandte Chemie International Edition Dr Tavassoli’s team and his collaborators, Dr Jeremy Blaydes and Professor Tom Brown, show that human cells can still read through strands of DNA correctly despite being stitched together using a linker not found in nature.The artificially linked DNA was created by joining oligonucleotides using click chemistry — chemistry tailored to mimic nature which generates substances quickly and reliably by joining small units together.This click technique is highly efficient and boasts a number of advantages over the usual approaches to assembling DNA strands in the lab using a combination of DNA synthesis, PCR amplification and enzymatic ligation.”As chemists we always sought to synthesise long strands of DNA but have been limited by our assumption that the phosphodiester bond is necessary for DNA to function in cells,” says Dr Tavassoli. The DNA backbone is made up of pentose sugars and phosphate groups that stitch the nucleotides together using phosphodiester bonds. This backbone acts as the scaffold for the four bases that make up the genetic code.The click DNA approach relies on a rapid and efficient stitching together of modified DNA strands using the copper-catalysed alkyne-azide cycloaddition reaction. Click-linking DNA leaves behind a triazole group in the backbone and it was feared that cellular machinery would be unable to read these unnaturally joined DNA strands. The new study demonstrated error-free transcription in human cells, the first example of a non-natural DNA linker working correctly in eukaryotic cells.”This is important because it shows that we don’t have to stick to the phosphodiester backbone of the DNA at the site of DNA ligation,” Dr Tavassoli explains. “This suggests that we can replace the enzymatic methods for DNA assembly and DNA ligation with highly efficient chemical reactions.””This is a mind blowing advance that demonstrates chemistry’s power to manipulate nature’s nature,” comments Nobel laureate Barry Sharpless at the Scripps Research Institute, US, who first described the click chemistry process. “I only dreamed I’d get to see click chemistry do this in my lifetime. It is a marvellous achievement.”Story Source:The above story is based on materials provided by University of Southampton. Note: Materials may be edited for content and length.

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Impaired cell division leads to neuronal disorder

Prof. Erich Nigg and his research group at the Biozentrum of the University of Basel have discovered an amino acid signal essential for error-free cell division. This signal regulates the number of centrosomes in the cell, and its absence results in the development of pathologically altered cells. Remarkably, such altered cells are found in people with a neurodevelopmental disorder, called autosomal recessive primary microcephaly. The results of these investigations have been published in the current issue of the US journal Current Biology.Normal separation of chromosomes (blue) with two centrosomes (red) in a bipolar spindel apparatus (green). Flawed separation of chromosomes (blue) with several centrosomes (red) in a multipolar spindel apparatus (green).Cell division is the basis of all life. Of central importance is the error-free segregation of genetic material, the chromosomes. A flawless division process is a prerequisite for the development of healthy, new cells, whilst errors in cell division can cause illnesses such as cancer. The centrosome, a tiny cell organelle, plays a decisive role in this process.Prof. Erich Nigg’s research group at the Biozentrum of the University of Basel has investigated an important step in cell division: the duplication of the centrosome and its role in the correct segregation of the chromosomes into two daughter cells. …

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Malignant Sarcomatoid Mesothelioma-What Is This?

In histological terms, there are four different types of mesothelioma: sarcomatoid, epithelial, biphasic, and desmoplastic (a variant of sarcomatoid).In medical terms, the term histopathology refers to the microscopic examination of cellular tissue to gain insight into the manifestations of various diseases.Malignant sarcomatoid mesothelioma is the least common of the four cellular types. It accounts for approximately 7 to 20 percent of cases. When viewed under a microscope,the malignant cells appear as elongated spindle-shaped cells that are irregularly shaped and often overlap one another.Desmoplastic mesothelioma is considered a variant of sarcomatoid mesothelioma. This form is likely the most difficult of all mesotheliomas to diagnose. When desmoplastic mesothelioma invades or metastasizes, the cells can appear very bland and can be misdiagnosed as benign fibrous tissue. Medical …

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Embryonic stem cells produced in living adult organisms

Sep. 11, 2013 — A team from the Spanish National Cancer Research Centre (CNIO) has become the first to make adult cells from a living organism and show characteristics of embryonic stem cells.Researchers have also discovered that these embryonic stem cells, obtained directly from the inside of the organism, have a broader capacity for differentiation than those obtained via in vitro culture. Specifically, they have the characteristics of totipotent cells: a primitive state never before obtained in a laboratory.The study, carried out by CNIO, was led by Manuel Serrano, the director of the Molecular Oncology Programme and head of the Tumoural Suppression Laboratory. The study was supported by Manuel Manzanares’s team from the Spanish National Cardiovascular Research Centre (CNIC).Embryonic stem cells are the main focus for the future of regenerative medicine. They are the only ones capable of generating any cell type from the hundreds of cell types that make up an adult organism, so they are the first step towards curing illnesses such as Alzheimer, Parkinson’s disease or diabetes. Nevertheless, this type of cell has a very short lifespan, limited to the first days of embryonic development, and they do not exist in any part of an adult organism.One of the greatest achievements in recent biomedical research was in 2006 when Shinya Yamanaka managed to create embryonic stem cells (pluripotent stem cells, induced in vitro, or in vitro iPSCs) in a laboratory from adult cells, via a cocktail of just four genes. Yamanaka’s discovery, for which he was awarded the Nobel Prize in Medicine in 2012, opened a new horizon in regenerative medicine.CNIO researchers have taken another step forward, by achieving the same as Yamanaka, but this time within the same organism, in mice, without the need to pass through in vitro culture dishes. Generating these cells within an organism brings this technology even closer to regenerative medicine.The first challenge for CNIO researchers was to reproduce the Yamanaka experiment in a living being. They chose a mouse as a model organism. Using genetic manipulation techniques, researchers created mice in which Yamanaka’s four genes could be activated at will. …

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Capturing brain activity with sculpted light

Sep. 9, 2013 — A major aim of today’s neuroscience is to understand how an organism’s nervous system processes sensory input and generates behavior. To achieve this goal, scientists must obtain detailed maps of how the nerve cells are wired up in the brain, as well as information on how these networks interact in real time.The organism many neuroscientists turn to in order to study brain function is a tiny, transparent worm found in rotting soil. The simple nematode C. elegans is equipped with just 302 neurons that are connected by roughly 8000 synapses. It is the only animal for which a complete nervous system has been anatomically mapped.Researchers have so far focused on studying the activity of single neurons and small networks in the worm, but have not been able to establish a functional map of the entire nervous system. This is mainly due to limitations in the imaging-techniques they employ: the activity of single cells can be resolved with high precision, but simultaneously looking at the function of all neurons that comprise entire brains has been a major challenge. Thus, there was always a trade-off between spatial or temporal accuracy and the size of brain regions that could be studied.Scientists at Vienna’s Research Institute of Molecular Pathology (IMP), the Max Perutz Laboratories (MFPL), and the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna have now closed this gap and developed a high speed imaging technique with single neuron resolution that bypasses these limitations. In a paper published online in Nature Methods, the teams of Alipasha Vaziri and Manuel Zimmer describe the technique which is based on their ability to “sculpt” the three-dimensional distribution of light in the sample. With this new kind of microscopy, they are able to record the activity of 70% of the nerve cells in a worm’s head with high spatial and temporal resolution.”Previously, we would have to scan the focused light by the microscope in all three dimensions,” says quantum physicist Robert Prevedel. …

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Preventing cancer? Team IDs two pathways through which chromosomes are rearranged

Sep. 8, 2013 — Biologists reported today in Nature that they have identified two pathways through which chromosomes are rearranged in mammalian cells. These types of changes are associated with some cancers and inherited disorders in people.”Our finding provides a target to prevent these rearrangements, so we could conceivably prevent cancer in some high-risk people,” said senior author Edward P. (Paul) Hasty, D.V.M., of the School of Medicine at The University of Texas Health Science Center at San Antonio. Partial funding came from the Cancer Therapy & Research Center at the UT Health Science Center San Antonio.The two pathways rearrange chromosomes by recombining DNA repeats that are naturally found in the genome, Dr. Hasty said. DNA, the chemical substance of genes, denatures and replicates during cell division and other processes. Repeats are sequences of DNA that are duplicated.Both pathways are important for the synthesis of DNA. “Therefore, we propose that chromosomal rearrangements occur as DNA is being synthesized,” Dr. Hasty said.The experiments were conducted with mouse embryonic stem cells grown in tissue culture. …

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Neuroscientists show that monkeys can decide to call out or keep silent

Sep. 6, 2013 — “Should I say something or not?” Human beings are not alone in pondering this dilemma — animals also face decisions when they communicate by voice. University of Tübingen neurobiologists Dr. Steffen Hage and Professor Andreas Nieder have now demonstrated that nerve cells in the brain signal the targeted initiation of calls — forming the basis of voluntary vocal expression.Share This:When we speak, we use the sounds we make for a specific purpose — we intentionally say what we think, or consciously withhold information. Animals, however, usually make sounds according to what they feel at that moment. Even our closest relations among the primates make sounds as a reflex based on their mood. Now, Tübingen neuroscientists have shown that rhesus monkeys are able to call (or be silent) on command. They can instrumentalize the sounds they make in a targeted way, an important behavioral ability which we also use to put language to a purpose.To find out how the neural cells in the brain catalyse the production of controled vocal noises, the researchers taught rhesus monkeys to call out quickly when a spot appeared on a computer screen. While the monkeys solved puzzles, measurements taken in their prefrontal cortex revealed astonishing reactions in the cells there. The nerve cells became active whenever the monkey saw the spot of light which was the instruction to call out. …

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Biologists uncover details of how we squelch defective neurons

Sep. 4, 2013 — Biologists at the University of California, San Diego have identified a new component of the cellular mechanism by which humans and animals automatically check the quality of their nerve cells to assure they’re working properly during development.In a paper published in this week’s issue of the journal Neuron, the scientists report the discovery in the laboratory roundworm C. elegans of a “quality check” system for neurons that uses two proteins to squelch the signals from defective neurons and marks them for either repair or destruction.”To be able to see, talk and walk, nerve cells in our body need to communicate with their right partner cells,” explains Zhiping Wang, the lead author in the team of researchers headed by Yishi Jin, a professor of neurobiology in UC San Diego’s Division of Biological Sciences and a professor of cellular and molecular medicine in its School of Medicine. “The communication is mediated by long fibers emitting from neurons called axons, which transmit electric and chemical signals from one cell to the other, just like cables connecting computers in a local wired network. In developing neurons, the journey of axons to their target cells is guided by a set of signals. These signals are detected by ‘mini-receivers’ — proteins called guidance receptors — on axons and translated into ‘proceed,’ ‘stop,’ ‘turn left’ or ‘turn right.’ Thus, the quality of these receivers is very important for the axons to interpret the guiding signals.”Jin, who is also an Investigator of the Howard Hughes Medical Institute, says defective protein products and environmental stress, such as hyperthermia, can sometimes jeopardize the health and development of cells. “This may be one reason why pregnant women are advised by doctors to avoid saunas and hot tubs,” she adds.The scientists discovered the quality check system in roundworms, and presumably other animals including humans, consists of two parts: a protein-cleaning machine containing a protein called EBAX-1, and a well-known protein assembly helper called heat-shock protein 90 known as “hsp90.””Hsp90 facilitates the assembly of guidance receivers during the production and also fixes flawed products whenever they are detected,” says Andrew Chisholm, a professor of neurobiology and cell and developmental biology, who also helped lead the study. “The EBAX-containing protein-cleaning machine is in charge of destroying any irreparable products so that they don’t hang around and affect the performance of functional receivers. The EBAX-1 protein plays as a defectiveness detector in this machine and a connector to Hsp90. It captures defective products and presents them for either repair or destruction.”A human neurodevelopmental disorder called “horizontal gaze palsy with progressive scoliosis” is associated with the defective production of one of the protein guidance receivers. …

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New laser-based tool could dramatically improve the accuracy of brain tumor surgery

Sep. 4, 2013 — A new laser-based technology may make brain tumor surgery much more accurate, allowing surgeons to tell cancer tissue from normal brain at the microscopic level while they are operating, and avoid leaving behind cells that could spawn a new tumor.In a new paper, featured on the cover of the journal Science Translational Medicine, a team of University of Michigan Medical School and Harvard University researchers describes how the technique allows them to “see” the tiniest areas of tumor cells in brain tissue.They used this technique to distinguish tumor from healthy tissue in the brains of living mice — and then showed that the same was possible in tissue removed from a patient with glioblastoma multiforme, one of the most deadly brain tumors.Now, the team is working to develop the approach, called SRS microscopy, for use during an operation to guide them in removing tissue, and test it in a clinical trial at U-M. The work was funded by the National Institutes of Health.A need for improvement in tumor removalOn average, patients diagnosed with glioblastoma multiforme live only 18 months after diagnosis. Surgery is one of the most effective treatments for such tumors, but less than a quarter of patients’ operations achieve the best possible results, according to a study published last fall in the Journal of Neurosurgery.”Though brain tumor surgery has advanced in many ways, survival for many patients is still poor, in part because surgeons can’t be sure that they’ve removed all tumor tissue before the operation is over,” says co-lead author Daniel Orringer, M.D., a lecturer in the U-M Department of Neurosurgery who has worked with the Harvard team since a chance meeting with a team member during his U-M residency.”We need better tools for visualizing tumor during surgery, and SRS microscopy is highly promising,” he continues. “With SRS we can see something that’s invisible through conventional surgical microscopy.”The SRS in the technique’s name stands for stimulated Raman scattering. Named for C.V. Raman, one of the Indian scientists who co-discovered the effect and shared a 1930 Nobel Prize in physics for it, Raman scattering involves allows researchers to measure the unique chemical signature of materials.In the SRS technique, they can detect a weak light signal that comes out of a material after it’s hit with light from a non-invasive laser. By carefully analyzing the spectrum of colors in the light signal, the researchers can tell a lot about the chemical makeup of the sample.Over the past 15 years, Sunney Xie, Ph.D., of the Department of Chemistry and Chemical Biology at Harvard University — the senior author of the new paper — has advanced the technique for high-speed chemical imaging. By amplifying the weak Raman signal by more than 10,000 times, it is now possible to make multicolor SRS images of living tissue or other materials. The team can even make 30 new images every second — the rate needed to create videos of the tissue in real time.Seeing the brain’s microscopic architectureA multidisciplinary team of chemists, neurosurgeons, pathologists and others worked to develop and test the tool. …

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Scientists edge closer towards first pancreatitis treatment

Sep. 3, 2013 — Scientists have for the first time provided proof of principle for a drug-based treatment of acute pancreatitis — a disease for which currently there is no treatment.Each year around 20,000 people in the UK are admitted to hospital with acute pancreatitis. One in five of these cases are severe, resulting in around 1000 deaths annually.Published today in the US-based PNAS journal, findings reveal that tests undertaken by scientists at Cardiff University, using an existing calcium channel-blocking compound developed by GlaxoSmithKline, have succeeded in markedly reducing the flow of calcium into isolated pancreatic cells and stopping the root cause of the disease in its tracks.”The aim of the research was to block excessive calcium entry caused by agents inducing pancreatitis and then test whether this would protect the pancreatic cells from self-digestion and death,” explains Senior Author of the research and Director of Cardiff University’s School of Biosciences, MRC Professor Ole Petersen FRS.”Our research shows that the calcium channel inhibiting compound offers unique and effective protection against inappropriate activation inside the cells of digestive enzymes, which would cannibalise the pancreas and the surrounding tissue.”This breakthrough shows huge potential to radically change and improve the outcome for patients suffering from severe pancreatitis. The publication of these findings will open the way for further research involving animals and humans — and, if successful, we shall for the first time be able to treat this often fatal disease.”The research was funded by a £2.3M Medical Research Council (MRC) Programme grant.Dr Joe McNamara Population and Systems Medicine Board Chair at the Medical Research Council who funded the study, said: “While further research will be needed to show that the success seen here in cells can be replicated in animal and then human trials, this is clearly an interesting study which takes an innovative first step towards drug development for acute pancreatitis, an increasingly common condition for which new treatment options are sorely needed.”Repeated attacks of acute pancreatitis can lead to chronic pancreatitis, which manifestly increases the risk of developing pancreatic cancer; currently one of the top four cancer killers in the UK. A treatment driven by this compound may also reduce the risk of patients developing pancreatic cancer.Previous research by Professor Petersen and his team has determined that processes inside isolated pancreatic cells leading to pancreatitis can be induced by the combination of alcohol and fat.When alcohol and fatty acids mix inside the pancreas, a massive release of calcium stored inside the pancreatic cells is triggered. The emptying of these calcium stores then sets in motion the opening of special channels in the cell membrane that allow calcium to enter the cells.The intrusion of this calcium causes activation of normally inactive digestive enzymes inside the cells, which in turn start digesting the pancreas and everything around it.

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An easier way to control genes

Sep. 3, 2013 — MIT researchers have shown that they can turn genes on or off inside yeast and human cells by controlling when DNA is copied into messenger RNA — an advance that could allow scientists to better understand the function of those genes.The technique could also make it easier to engineer cells that can monitor their environment, produce a drug or detect disease, says Timothy Lu, an assistant professor of electrical engineering and computer science and biological engineering and the senior author of a paper describing the new approach in the journal ACS Synthetic Biology.”I think it’s going to make it a lot easier to build synthetic circuits,” says Lu, a member of MIT’s Synthetic Biology Center. “It should increase the scale and the speed at which we can build a variety of synthetic circuits in yeast cells and mammalian cells.”The new method is based on a system of viral proteins that have been exploited recently to edit the genomes of bacterial and human cells. The original system, called CRISPR, consists of two components: a protein that binds to and slices DNA, and a short strand of RNA that guides the protein to the right location on the genome.”The CRISPR system is quite powerful in that it can be targeted to different DNA binding regions based on simple recoding of these guide RNAs,” Lu says. “By simply reprogramming the RNA sequence you can direct this protein to any location you want on the genome or on a synthetic circuit.”Lead author of the paper is Fahim Farzadfard, an MIT graduate student in biology. Samuel Perli, a graduate student in electrical engineering and computer science, is also an author.Targeting transcriptionIn previous studies, CRISPR has been used to snip out pieces of a gene to disable it or replace it with a new gene. Lu and his colleagues decided to use the CRISPR system for a different purpose: controlling gene transcription, the process by which a sequence of DNA is copied into messenger RNA (mRNA), which carries out the gene’s instructions.Transcription is tightly regulated by proteins called transcription factors. These proteins bind to specific DNA sequences in the gene’s promoter region and either recruit or block the enzymes needed to copy that gene into mRNA.For this study, the researchers adapted the CRISPR system to act as a transcription factor. First, they modified the usual CRISPR protein, known as Cas9, so that it could no longer snip DNA after binding to it. They also added to the protein a segment that activates or represses gene expression by modulating the cell’s transcriptional machinery.To get Cas9 to the right place, the researchers also delivered to the target cells a gene for an RNA guide that corresponds to a DNA sequence on the promoter of the gene they want to activate.The researchers showed that once the RNA guide and the Cas9 protein join together inside the target cell, they accurately target the correct gene and turn on transcription. …

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The ‘weakest link’ in the aging proteome

Sep. 3, 2013 — Proteins are the chief actors in cells, carrying out the duties specified by information encoded in our genes. Most proteins live only two days or less, ensuring that those damaged by inevitable chemical modifications are replaced with new functional copies.In a new study published August 29 in Cell, a team led by researchers at the Salk Institute for Biological Studies and The Scripps Research Institute (TSRI) have now identified a small subset of proteins in the brain that persist for longer, even more than a year, without being replaced. These long-lived proteins have lifespans significantly longer than the typical protein, and their identification may be relevant to understanding the molecular basis of aging.”Protein longevity can be a major contributor to cellular aging,” says Martin Hetzer, a professor in Salk’s Molecular and Cell Biology Laboratory and holder of the Jesse and Caryl Philips Foundation Chair, who was a senior author of the study with TSRI Professor John Yates. “Simply identifying all long-lived proteins allows us to focus our studies on these specific proteins, which may be the weakest link in the aging proteome.”The study provides the first comprehensive and unbiased identification of the long-lived proteome, the entire set of proteins expressed by a genome under a given set of environmental conditions. In a study published in Science last year, Hetzer and his colleagues identified long-lived proteins in one sub-cellular location, namely the nucleus.The new study takes the Science findings one step further by providing a system-wide identification of proteins with long lifespans in the rat brain, a laboratory model of human biology. The scientists found that long-lived proteins included those involved in gene expression, neuronal cell communication and enzymatic processes, as well as members of the nuclear pore complex (NPC), which is responsible for all traffic into and out of the nucleus.Furthermore, they found that the NPC undergoes slow but finite turnover through the exchange of smaller sub-complexes, not whole NPCs, which may help clear inevitable accumulation of damaged components.”This can be thought of as similar to maintaining a car, where you don’t replace the entire car, just the components that have broken down,” says lead study author Brandon Toyama, a postdoctoral fellow in Hetzer’s laboratory.Hetzer and his colleagues previously found that NPC deterioration might be a general aging mechanism leading to age-related defects in nuclear function. Other laboratories have linked protein homeostasis, or internal stability, to declining cell function and, thus, disease. The new findings reveal cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process.”Now that we have identified these long-lived proteins, we can begin to examine how they may be affected in aging and what the cell does to compensate for inevitable damage,” says Toyama.Hetzer’s team is now identifying targets that are involved in aging and potential pathways to address this. “We’re starting to think about how to get functionality back to that younger version of the protein,” he says.Other researchers on the study were Jeffery N. …

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Harmonizing a broken heart: Stem cells keep cardiac beat in synchrony

Sep. 1, 2013 — Stem cell therapy used to regenerate injured tissue in the heart restores synchronous pumping, shows research published today [1 September] in The Journal of Physiology. The study proposes a novel strategy of ‘biological resynchronisation’ in which stem cells repair heart muscle damage to reestablish correct cardiac motion.Heart attacks limit local oxygen, which can kill areas of cardiac tissue — called ‘infarcted’ areas — and also leave scarring. This damage leads to a lack of synchrony in the heart beat motion.Current therapies use pacing devices, but these require healthy tissue for optimal outcome, meaning a third of patients do not respond well to this treatment. However, this new approach discovered by a team at Mayo Clinic in Rochester, Minnesota, USA overcomes this limitation as stem cells actually form functional cardiac tissue and reconstruct heart muscle.Professor Andre Terzic, who led the study, explains the importance of this potential new therapy: “Heart chambers must beat in synchrony to ensure proper pumping performance. Damage to the heart can generate inconsistent wall motion, leading to life-threatening organ failure.”The heart is vulnerable to injury due to a limited capacity for self-repair. Current therapies are unable to repair damaged cardiac tissue. This proof-of-principle study provides evidence that a stem cell-based regenerative intervention may prove effective in synchronizing failing hearts, extending the reach of currently available therapies.”Doctor Satsuki Yamada, first author of the study, further explains how the research was carried out:”Stem cells, with a capacity of generating new heart muscle, were engineered from ordinary tissue. These engineered stem cells were injected into damaged hearts of mice. The impact on cardiac resynchronization was documented using high-resolution imaging.”The observed benefit, in the absence of adverse effects, will need to be validated in additional pre-clinical studies prior to clinical translation.

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Balancing act: Cell senescence, aging related to epigenetic changes

Aug. 30, 2013 — One way cells promote tumor suppression is through a process called senescence, an irreversible arrest of proliferation. Senescence is thought to be associated with normal aging, but is also a protective measure by the body against run-away cell replication. Studying the basic science of senescence gives biomedical researchers a better understanding of the mechanisms behind age-related diseases such as cancer.Researchers from the Perelman School of Medicine at the University of Pennsylvania have found that epigenetic factors play a role in senescence. Epigenetic factors act on the structures in which genes reside, called chromatin. They found that senescent cells appear to undergo changes in their chromatin and find similar changes in cells that are prematurely aging.Their observations take place deep within cells — inside the chromatin of a cell’s nucleus. In the chromatin, DNA is wound around proteins called histones. Enzymes called histone modifiers mark the chromatin — like using sticky notes as reminders — to open up or close down regions of the genome, which makes these areas more or less available to be “read” as a gene. (Epigenetics is the science of how gene activity can be altered without actual changes in DNA sequence.)Shelley Berger, PhD, professor of Cell and Developmental Biology, Parisha Shah, PhD, a postdoctoral fellow in the Berger lab, and colleagues, compared differences in the presence of the genome-wide sticky notes between two lung cell populations, one at the start of proliferation, as a control, and the other at the end of its replication cycle and senescent. Berger is also director of the Penn Epigenetics Program.They found that when a nuclear protein called lamin B1 is deleted in senescent cells, large-scale changes in gene expression, and likely chromatin, occurred. …

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Protein that protects nucleus also regulates stem cell differentiation

Aug. 29, 2013 — The human body has hundreds of different cell types, all with the same basic DNA, and all of which can ultimately be traced back to identical stem cells. Despite this fundamental similarity, a bone cell has little in common with a brain cell when it comes to appearance or function. The fact that bone is rigid and mechanically distinct from soft fat or brain had been speculated to play some role in differentiation to new cells in those parts of the body, but mechanisms have been unclear.Now, a study by researchers at the University of Pennsylvania have shown that a protein found in the nuclei of all cells — lamin-A — plays a key role in the differentiation process.The study was led by professor Dennis Discher and postdoctoral researchers Joe Swift and Irena Ivanovska of the Department of Chemical and Biomolecular Engineering in Penn’s School of Engineering and Applied Science.It was published in the journal Science.Lamin-A is a protein found in the nucleus of all adult cells. This rope-like protein forms a protective netting around the DNA contained at the core of the nucleus.The first hint that lamin-A might be involved in regulating the stiffness of nuclei came from diseases that lead to abnormal protein. One such disease, progeria, has symptoms akin to premature aging, including brittle bones and muscle wasting. But while these stiff tissues are affected, soft tissues such as brain and blood remain normal.As a self-assembling filament, lamin-A is like a rope in that, when it is pulled, it becomes taut. As this stiffness would be better suited to resisting the pull of neighboring cells, the researchers speculated that such a protein would be more abundant in tissues, like bone, cartilage and muscle, that need to be stiff to resist the stresses and strains of everyday activity.”We hypothesized that higher levels of lamin-A in the nuclei of stiffer tissues would be appropriate to a greater need to prevent breakage of the precious DNA surrounded by the lamin-A net,” Discher said.To determine how levels of lamin-A varied between cell types, the researchers took tissue cells from both mice and humans, broke the cells apart and fed them to a mass spectrometer to quantify the many protein components.The researchers then looked for any correlation between the amounts of the numerous proteins detected and the elasticity of the source tissue. Since the material outside cells called extracellular matrix is known to be particularly abundant in stiff tissues like bone and cartilage, they expected to see correlations with matrix proteins like collagen. However, they also found evidence supporting their hypothesis that nuclear lamin-A levels also increase dramatically from softer to more rigid tissues.”The mass spectrometry lets us look at and quantify hundreds of proteins at the same time,” Swift said. …

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‘Mini human brains’ created: Scientists grow human brain tissue in 3-D culture system

Aug. 29, 2013 — Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of Nature allows pluripotent stem cells to develop into cerebral organoids — or “mini brains” — that consist of several discrete brain regions.Instead of using so-called patterning growth factors to achieve this, scientists at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the “mini brains,” the scientists were also able to model the development of a human neuronal disorder and identify its origin — opening up routes to long hoped-for model systems of the human brain.The development of the human brain remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain’s development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has just changed that.Brain Size MattersStarting with established human embryonic stem cell lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. …

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Why are some cells more cancer prone?

Aug. 27, 2013 — Cells in the body wear down over time and die. In many organs, like the small intestine, adult stem cells play a vital role in maintaining function by replacing old cells with new ones. Learning about the nature of tissue stem cells can help scientists understand exactly how our organs are built, and why some organs generate cancer frequently, but others only rarely.New work from Carnegie’s Alexis Marianes and Allan Spradling used some of the most experimentally accessible tissue stem cells, the adult stem cells in the midsection of the fruit fly gut, with surprising results. Their findings are published by eLife.Like the small intestine in mammals, the midgut of fruit flies is where most digestion takes place. Scientists had noticed a few regions in both the midgut and small intestine were specialized for certain tasks, such as absorbing iron, but had little understanding of the extent of these regional differences or how they were maintained.Marianes and Spradling were able to demonstrate that there are 10 different major subregions within the fruit fly midgut. They occur in a specific order and each is responsible for different digestive and nutrient-storage processes, as evidenced by the expression of many specific genes. Most importantly, the adult stem cells in each region are specialized as well, and only support the types of cells found within it. Thus, during development, achieving the right spatial sequence of stem cells is probably critical to causing intestines to be built and maintained in order to function optimally.The researchers also showed that tumors arise preferentially in specific regions of the midgut, a phenomenon well known in oncology. They showed the tumor-prone regions were specialized for lipid absorption, and stem cell function in them differed in small ways from stem cell function in other regions.This work will motivate the search for fine-grained specialization in both tissue organization and in stem cells within many mammalian tissues. …

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Novel way gene controls stem cell self-renewal

Aug. 25, 2013 — Stem cell scientists at the Princess Margaret Cancer Centre have discovered the gene GATA3 has a role in how blood stem cells renew themselves, a finding that advances the quest to expand these cells in the lab for clinical use in bone marrow transplantation, a procedure that saves thousands of lives every year.Share This:The research, published online today in Nature Immunology, provides an important piece in the puzzle of understanding the mechanisms that govern the blood stem cell self-renewal process, says principal investigator Norman Iscove, Senior Scientist at the Princess Margaret, University Health Network (UHN). Dr. Iscove is also an investigator at UHN’s McEwen Centre for Regenerative Medicine and a Professor in the Faculty of Medicine, University of Toronto.”Researchers have known for a long time that stem cells can increase their numbers in the body through self-renewal; however, it has proven very difficult to establish conditions for self-renewal in the laboratory,” says Dr. Iscove. Indeed, he explains, the quest to do so has been a holy grail for stem cell researchers because the very effectiveness, safety and availability of the transplantation procedure depend on the number of stem cells available to transplant.In the lab and using genetically engineered mice, the Iscove team zeroed in on GATA3 and determined that interfering with its function causes stem cells to increase their self-renewal rate and thereby results in increased numbers of stem cells. Dr. Iscove expects scientists will be able to use this new information to improve their ability to grow increased numbers of blood stem cells for use in bone marrow transplantation and possibly, gene therapy.Dr. Iscove’s research is a new page in the growing volume of stem cell science that began here in 1961 with the ground-breaking discovery of blood-forming stem cells by Drs. James Till and the late Ernest McCulloch. …

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Drug delivery: Why gold nanoparticles can penetrate cell walls

Aug. 22, 2013 — Cells are very good at protecting their precious contents — and as a result, it’s very difficult to penetrate their membrane walls to deliver drugs, nutrients or biosensors without damaging or destroying the cell. One effective way of doing so, discovered in 2008, is to use nanoparticles of pure gold, coated with a thin layer of a special polymer. But nobody knew exactly why this combination worked so well, or how it made it through the cell wall.Now, researchers at MIT and the Ecole Polytechnique de Lausanne in Switzerland have figured out how the process works, and the limits on the sizes of particles that can be used. Their analysis appears in the journal Nano Letters, in a paper by graduate students Reid Van Lehn, Prabhani Atukorale, Yu-Sang Yang and Randy Carney and professors Alfredo Alexander-Katz, Darrell Irvine and Francesco Stellacci.Until now, says Van Lehn, the paper’s lead author, “the mechanism was unknown. … In this work, we wanted to simplify the process and understand the forces” that allow gold nanoparticles to penetrate cell walls without permanently damaging the membranes or rupturing the cells. The researchers did so through a combination of lab experiments and computer simulations.The team demonstrated that the crucial first step in the process is for coated gold nanoparticles to fuse with the lipids — a category of natural fats, waxes and vitamins — that form the cell wall. The scientists also demonstrated an upper limit on the size of such particles that can penetrate the cell wall — a limit that depends on the composition of the particle’s coating.The coating applied to the gold particles consists of a mix of hydrophobic and hydrophilic components that form a monolayer — a layer just one molecule thick — on the particle’s surface. Any of several different compounds can be used, the researchers explain.”Cells tend to engulf things on the surface,” says Alexander-Katz, an associate professor of materials science and engineering at MIT, but it’s “very unusual” for materials to cross that membrane into the cell’s interior without causing major damage. Irvine and Stellacci demonstrated in 2008 that monolayer-coated gold nanoparticles could do so; they have since been working to better understand why and how that works.Since the nanoparticles themselves are completely coated, the fact that they are made of gold doesn’t have any direct effect, except that gold nanoparticles are an easily prepared model system, the researchers say. …

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