June 13, 2017 Mitochondria are tiny, free-floating organelles inside cells. New Northwestern Medicine research has discovered that they play an important role in hematopoiesis, the bodys process for creating new blood cells. Credit: Northwestern University

New Northwestern Medicine research published in Nature Cell Biology has shown that mitochondria, traditionally known for their role creating energy in cells, also play an important role in hematopoiesis, the body's process for creating new blood cells.

"Historically, mitochondria are viewed as ATPenergyproducing organelles," explained principal investigator Navdeep Chandel, PhD, the David W. Cugell Professor of Medicine in the Division of Pulmonary and Critical Care Medicine. "Previously, my laboratory provided evidence that mitochondria can dictate cell function or fate independent of ATP production. We established the idea that mitochondria are signaling organelles."

In the current study, Chandel's team, including post-doctoral fellow Elena Ans, PhD, and graduate students Sam Weinberg and Lauren Diebold, demonstrated that mitochondria control hematopoietic stem cell fate by preventing the generation of a metabolite called 2-hydroxyglutarate (2HG). The scientists showed that mice with stem cells deficient in mitochondrial function cannot generate blood cells due to elevated levels of 2HG, which causes histone and DNA hyper-methylation.

"This is a great example of two laboratories complementing their expertise to work on a project," said Chandel, also a professor of Cell and Molecular Biology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Paul Schumacker, PhD, professor of Pediatrics, Cell and Molecular Biology and Medicine, was also a co-author on the paper.

Chandel co-authored an accompanying paper in Nature Cell Biology, led by Jian Xu, PhD, at the University of Texas Southwestern Medical Center, which demonstrated that initiation of erythropoiesis, the production of red blood cells specifically, requires functional mitochondria.

"These two studies collectively support the idea that metabolism dictates stem cell fate, which is a rapidly evolving subject matter," said Chandel, who recently wrote a review in Nature Cell Biology highlighting this idea. "An important implication of this work is that diseases linked to mitochondrial dysfunction like neurodegeneration or normal aging process might be due to elevation in metabolites like 2HG."

Explore further: Novel method enables absolute quantification of mitochondrial metabolites

More information: Elena Ans? et al. The mitochondrial respiratory chain is essential for haematopoietic stem cell function, Nature Cell Biology (2017). DOI: 10.1038/ncb3529

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Mitochondria behind blood cell formation - Phys.org - Phys.Org

June 14, 2017

Female babies are born with a full set of egg precursors in their ovaries, yet the molecular mechanism by which these cells proliferate during embryonic development was unclear. Now, using a mouse model created at A*STAR, an international team of researchers has pinpointed the regulatory factors needed for this rapid cell division to occur in the developing female gonad.

"We have paved the way to study different cell cycle regulatory pathways that may go awry during development," says study author Philipp Kaldis, a senior principal investigator at the A*STAR Institute of Molecular and Cell Biology. Future research in this area, he notes, could lead to new treatments for cancer and infertility.

The embryonic cells that give rise to eggs are known as primordial germ cells, or PGCs. In micewhich have a similar but faster gestation than humansPGCs are identifiable at around the 7th day of development. By day 8, these cells temporarily stop dividing as they migrate inside the embryo. Then, around day 9.5, the cells enter a three-day period of frenetic growth in which they duplicate every 12 hours and the total number of PGCs increases around 50-fold.

Kaldis suspected that a protein called MASTL might be involved in this 72-hour bonanza of cell division since he and others had previously shown that MASTL is essential for the cell cycle to move forward in other cell types and other species.

He thus genetically engineered a mouse in which he could selectively delete the gene encoding MASTL from PGCs. Kaldis then sent the mice to Kiu Liu and Sanjiv Risal at the University of Gothenberg in Sweden, and collectively they showed that the PGCs in these mice could not complete the anaphase step in the cell cycle, in which the duplicated sets of chromosomes are meant to separate inside the dividing cell.

As a result, the PGCs were defective and died instead of multiplying. However, Kaldis and his team showed that proper cell division could be restored in the MASTL-deficient mice if they simultaneously wiped out another cell cycle regulator called PP2A.

The researchers concluded that MASTL normally functions to suppress the activity of PP2A to enable anaphase to proceed properly. And since defects in these germ cells often lead to tumors or infertility, it's possible, Kaldis notes, that MASTL and PP2A are implicated in these health problems as well. "We hope this work will stimulate new research in PGCs," he says.

Explore further: A protein that ensures correct chromosome segregation during cell division can lead to cancer if mutated

More information: Sanjiv Risal et al. MASTL is essential for anaphase entry of proliferating primordial germ cells and establishment of female germ cells in mice, Cell Discovery (2017). DOI: 10.1038/celldisc.2016.52

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Regulatory protein ensures that egg precursor cells boost their numbers during embryonic development - Phys.Org

Why mosquito-borne dengue virus causes more severe disease in some individuals, including hemorrhagic fever with or without shock, remains controversial and researchers are focusing on the factors related to the interaction between the virus and the host immune system, including the role of mast cells.

An in-depth review of the latest research showing how mast cells can be both protective and can contribute to the most severe forms of dengue is presented in the article Role of Mast Cells in Dengue Virus Pathogenesis, published in DNA and Cell Biology, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. The article is available free on the DNA and Cell Biology website through July 3, 2017.

Coauthors Berlin Londono-Renteria, Kansas State University, Manhattan, KS, Julio Marinez-Angarita, Instituto Nacional de Salud, Bogota, Colombia, and Andrea Troupin and Tonya Colpitts, University of South Carolina School of Medicine, Columbia, SC, study how mast cells recognize and interact with dengue virus and how mosquito saliva may affect the degranulation response of mast cells and the local immune responses during dengue virus infection in human skin. The researchers provide insights on what occurs during the early stages of dengue transmission and the mechanisms involved in mast cell activation and degranulation, which can increase the permeability of the human vasculature, causing it to become leaky.

Mast cells are best known for their roles in allergies (such as pollen or food) and, for rare people, sensitivity to the saliva injected by mosquitos during bites. In this BIT, Colpitts and co-authors demonstrate the contributions of these cells to the pathogenesis of dengue, a severe disease, says Carol Shoshkes Reiss, PhD, Editor-in-Chief of DNA and Cell Biology and Professor, Departments of Biology and Neural Science, and Global Public Health at New York University, NY. Understanding this may lead us to new approaches to the treatment of dengue fever and dengue shock syndrome. The latter secondary infection can be life-threatening.

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Dengue: Do mast cells contribute to more severe disease? - Outbreak News Today

Decades of research into characterization, prevention, detection and treatment have substantially expanded our collective understanding of cancer biology. However, these insights elicit a new generation of unanswered questions about the complexity of this group of often-deadly diseases. Historical investigations yielded the key understandings that cancer cells arise from indigenous cells, and most, if not all, tumors are derived from a single parent cell1. In 2000, Hanahan and Weinberg simplified the many aspects of transformation from normal human cells into cancerous ones through six essential cell physiology alterations. These so-called hallmarks of cancer include self-sufficiency in growth signals, insensitivity to anti-growth or inhibitory signals, evasion of apoptosis, unlimited replication capability, sustained angiogenesis, and tissue invasion and metastasis2. They later added deregulating cellular energetics and avoiding immune destruction as emerging hallmarks; genome instability and mutation and tumor-promoting inflammation as enabling characteristics3. The impact of external stimuli, interactions with neighboring cells and the extracellular matrix (ECM), heterogeneity, inherited traits, and other factors further complicate the elucidation of cancer biology.

Along with the expanding scope of research interests, methodologies have evolved to include live cell studies in addition to conventional biochemical and fixed cell assays. Live cell assays allow researchers to dynamically study a cells function in an environment that better represents in vivo conditions. Kinetic imaging of live cells provides a useful framework in which to gather meaningful details of cellular dynamics in real time, however, applications are often constrained by the limited versatility of available instruments. Most imaging systems are not suitable for capturing the widely ranging timelines in which cellular events occur from sub-second responses to events manifesting over days or weeks. Thus, multiple, dedicated instruments or bulky external accessories are often required, taking up precious bench space. Similarly, integrated image processing and data analysis is frequently limited or requires additional software to properly quantify the captured information.

Here, we describe an automated live cell imager designed for a wide range of temporal dynamics in live cell assays. Specifically, we demonstrate its capabilities for short-, medium- and long-term kinetic assays typically used when investigating cancer hallmarks. The integrated design of this system precludes the use of multiple instruments, while the advanced image capture and data analysis features deliver powerful and actionable insights.

Dysregulation of cellular signaling is a significant foundation for most of the aforementioned hallmarks of cancer4. Capturing a rapid, short-lived signaling event, such as calcium flux following GPCR activation, requires high temporal resolution. The automated live cell imager provides image capture rates of up to 20 frames per second, while in-line injectors enable reagent addition with continuous monitoring of cellular response. In the provided calcium mobilization example, we characterize the ATP-induced activation of endogenously expressed P2Y receptors in HeLa cells, using the cell membrane permeable calcium indicator dye Fluo-4 AM. Binding of calcium ions to Fluo-4 causes a structural change that results in a significant increase in fluorescence quantum yield and more than a hundred-fold increase in fluorescence relative to the unbound state. Per Figure 1, ATP (10 M final) was injected at t=5 seconds, an increase in intracellular calcium was detected approximately 3 seconds after the addition, and peak calcium mobilization for the entire field of cells was reached 13 seconds post-ATP addition. Image preprocessing and object masking tools reduced background fluorescence and a generated a larger assay window compared to total fluorescence measurements, resulting in a seven-fold increase in relative Fluo-4 fluorescence following ATP addition.

The relationship between wound healing and tumorigenesis is well-established5,6. Additionally, although migration is a function of normal cells, it is considered one of the hallmarks of cancer when dysregulated signals lead to cancer metastasis. Scratch assays are widely used to investigate in vitro cell migration and wound healing, where a monolayer cell culture is manually scratched to generate an area free of cells into which surrounding cells can migrate and proliferate. The imaging chamber of the automated live cell imager maintains cell health through consistent environmental conditions, including temperature, gas and humidity levels, over the entire incubation period, which is cell-dependent, but typically lasts no more than twenty-four hours. Automated phase contrast (label-free) imaging tracks the migratory characteristics of the cell model at pre-determined time points, while advanced software automatically places object masks to track parameters such as object size, area and total signal over the incubation period. In the provided scratch assay example, an approximately 500 m wide wound was created using HT-1080 fibrosarcoma cells and ibidi culture inserts. Per Figure 2A, the wound was treated with different concentrations of the migration inhibitor, cytochalasin D; and kinetic images were captured over twenty-four hours, while the cells were incubated under controlled conditions of 37 C, 5 percent CO2. Percent confluency was calculated (Figure 2B), showing that wound closure inhibition is proportional to cytochalasin D concentration, to the point where cytotoxicity begins to affect the cells neighboring the wound.

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Revealing New Details of Cancer Biology with Automated Kinetic Live Cell Imaging - Bioscience Technology

June 13, 2017 Credit: The Scripps Research Institute

Scientists at The Scripps Research Institute (TSRI) have solved a cellular mystery that may have important implications for fundamental biology and diseases like ALS. Their new research suggests that RNA may be the secret ingredient that helps cells to assemble, organize internal architecture, and ultimately dissolve dynamic droplet-like compartments.

These droplet-like structures are commonly known as membraneless organelles, and they are key to how cells compartmentalize their biochemistry and regulate processes such as gene expression and response to stress.

For 200 years, scientists have known of the existence of membraneless organelles in cells and wondered how they are regulated. Recent studies suggested that increasing the fraction of RNA can lead to the formation of protein-RNA droplets by a process called liquid-liquid phase separation.

"It is basically the same type of immiscibility phenomenon that drives oil to form droplets in water," said TSRI Associate Professor Ashok Deniz, who co-led the study published recently in the journal Angewandte Chemie as a Very Important Paper (VIP). "While several weak biomolecular forces collectively result in protein-RNA droplet formation, we focused on one particular type in this study: electrostatic interactions driven by oppositely charged biomolecules. A major discovery was that further increase in RNA concentration can dissolve these droplets, bringing back a homogeneous liquid phase."

The speed at which these droplets form and dissolve may be key to cellular survival. "Droplets can form and dissolve as they are needed, which allows cells to adapt very quickly to cellular stress," said Research Associate Priya Banerjee, who co-led the study and served as co-first author with graduate students Anthony N. Milin and Mahdi Muhammad Moosa of TSRI.

The new study suggests that the negative charge of RNA molecules is a key to both creating and dissolving droplets. "RNA is like a double agent," said Banerjee.

How Droplets Form and Disappear

RNA has an overall negative charge. When it initially comes in contact with positively-charged proteins, the oppositely charged molecules attract each other. Together, they create a molecular assembly and form liquid droplets. These droplets allow cells to carry out important functions.

The researchers also found that droplets will quickly dissolve when one increases RNA in the system.

"Adding more RNA to this system disrupts the fine balance between negative and positive charges, leading to the formation of negatively-charged assemblies that now repel each other, thus dissolving the droplet," said study co-author Paulo L. Onuchic, a graduate student in the Deniz Lab.

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This unique finding sheds light on an unexpected regulatory pathway. The research also challenges the previous conception that biomolecular forces that create droplets should be reversed to dissolve them. Instead of reversing the processthrough either removal of RNA or posttranslational modification of the protein to destroy its positive chargethe researchers found that the system can simply add more RNA to dissolve a droplet.

"The window-like behavior of droplet formation as a function of RNA concentration observed here exhibits a unidirectional route that can be exploited by cells using processes such as transcription," said Banerjee.

In further experiments, the team demonstrated that RNA synthesis by cellular machineries indeed forms and dissolves these droplets.

Creating "Hollow" Droplets

The fact that RNA can dissolve droplets gave the researchers a unique chance to control RNA addition and watch the dissolution process. "To our surprise, instead of a simple process of droplet dissolution, we observed hollow spheres forming inside droplets. Taking a step back, you see that by adding more RNA, we are creating low-density droplets inside high-density droplets," said Deniz.

Deniz compared this phenomenon to an ice cube melting from the inside. Interestingly, these internal droplets, called vacuoles, resemble the complex internal substructures that are typically observed in a number of cellular droplet-like organelles.

"The key to creating vacuoles is this unidirectional transition from an initial homogeneous liquid to two immiscible liquid phases and back to a homogeneous phase just by increasing the fraction of RNA," added Banerjee.

The team went on to test whether these findings would apply to a key protein found in stress-granules, important "droplet" organelles that protect cells during stress. They investigated an RNA-binding protein called FUS, which has been implicated in ALS.

"With FUS, we found that RNA can both form and dissolve droplets in the same fashion as the simpler model system. Remarkably, FUS droplets also exhibited complex internal substructures, which paves the way for ascertaining the biological role of these vacuoles," said Milin.

While this research is still in its early stages, the researchers believe mutations in FUS may interfere in the normal droplet dynamics in some patients with ALS, possibly stopping their cells from coping properly with cellular stress.

The work opens a number of avenues for future research in cell biology and disease, including quantitative studies of this specific type of phase transition in other biological systems, understanding the molecular determinants in proteins and RNA that control the droplet dynamics, and further studies of complex patterning of droplets.

Explore further: Acetone experiences Leidenfrost effect, no hotplate needed

More information: Priya R. Banerjee et al. Reentrant phase transition drives dynamic substructure formation in ribonucleoprotein droplets, Angewandte Chemie International Edition (2017). DOI: 10.1002/anie.201703191

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Scientists solve a mystery in cellular 'droplet' organelles - Phys.org - Phys.Org