From gene editing to stimulating the body’s innate mechanisms of tissue repair, Duke scientists and engineers are tackling different ways to someday provide treatments for patients with injury or degeneration of musculoskeletal tissues.
Watch this brief video which features Drs. Ben Alman, Shyni Varghese, and Charlie Gersbach of Regeneration Next. Each researcher is working on a strategy that could help us get closer to a regenerative medicine-based treatment for bone or joint tissue damage.
Regeneration Next is pleased to announce seven travel awards to assist graduate students in traveling to scientific conferences. The students will present tissue regeneration-related work in a variety of different research areas, at national and international conferences. This is the third cycle of travel grants supported by Regeneration Next. Read about the winners of Cycle One and Cycle Two to see what we’ve supported in the past. The next deadline for applications is September 17, 2018. Details are here>
The winners of the Regeneration Next travel awards are:
Emily Bowie, Goetz lab. “Primary cilia regulation of adult neuron homeostasis,” presenting at the EMBO Workshop – Cilia meeting in Copenhagen, Denmark.
Caley Burrus, Eroglu lab. “Striatal projection neurons require huntingtin for synaptic connectivity and longevity,” presenting at the Gordon Research Conference on Cellular and Molecular Neurobiology in Hong Kong.
Woonyung Hur, DiTalia Lab. “Cyclin-dependent 2 driven phase separation regulates histone locus body assembly,” presenting at the Cell Cycle Meeting in La Jolla, California.
Fei Sun, Poss lab. “Organ crosstalk during cardiac regeneration in zebrafish,” presenting at The Molecular and Cellular Basis of Tissue Regeneration and Repair meeting in Malta.
Susan Wopat, Bagnat lab. “Spine patterning is guided by segmentation of the notochord sheath,” presenting at the International Zebrafish Conference in Madison, WI.
Albert Zhang, Yan Lab. “The regulation of gliogenesis in C. elegans by lin-32,” presenting at the Gordon Research Conference on Cellular and Molecular Neurobiology in Hong Kong.
Hazel Zhang, Alman lab. “Role of glutamine metabolism in cartilage tumors,” presenting at the Gordon Research Conference on Bone and Teeth in Galveston, TX.
The walls of our guts are lined with finger-like protrusions called villi (green), which absorb nutrients from our food, and pockets called crypts (purple), which provide homes to stem cells. Duke cellular biologist Kaelyn Sumigray wants to know how the crypts get their pitted shape. In a new study on mice, she found that specific genes direct rows of cells to constrict on one side and expand on the other, forming curves in the intestinal wall like the bending of a slinky. Understanding how these crypts form will help researchers figure out their role in nurturing adult stem cells.
This gorgeous image comes from a recent paper, published May 3rd, in the journal Developmental Cell, describing Dr. Sumigray and her colleagues’ findings about how gut crypts form.
The journal also featured a Meet the Author Q&A about Dr. Sumigray. You can read more about Dr. Sumigray and what motivates her research in this interview here>
We are thrilled to announce our Regeneration Next Postdoctoral Fellows, 2019- 2021! This impressive third cohort consists of four Fellows chosen from a competitive pool of fifteen applicants. Their research interests are wide, ranging from liver regeneration, to bone formation, to nervous system repair and the mechanisms behind ALS (Lou Gehrig’s disease). They join the inaugural cohort and the 2018 – 2020 Fellows in shaping and growing the tissue regeneration community at Duke University. Congratulations to all of them!
Mariah Hoye, Ph.D.
Mariah Hoye received her PhD from Washington University in Saint Louis, MO where she studied the role of small, non-coding RNAs in motor neurons and their relation to the motor neuron degenerative disease, Amyotrophic Lateral Sclerosis (ALS). For her postdoctoral training, she will be working in the laboratory of Dr. Debra Silver in the Molecular Genetics and Microbiology department at Duke. As an RNI fellow, Mariah seeks to understand the RNA metabolism of neural stem cells that is required for proper brain development and how aberrations to stem cell RNA metabolism can lead to neurodevelopmental disorders and brain cancers.
Guoli Hu, Ph.D.
Guoli received his PhD in Cell Biology at Shanghai Jiao Tong University, in China. He recently accepted a postdoctoral associate position in the Department of Orthopaedic Surgery at Duke’s School of Medicine, where he works in Dr. Courtney Karner’s lab. His current research focuses on understanding the role of glutaminase (GLS) in regulating mesenchymal stem cell specification and differentiation into osteoblasts. With the support of the Regeneration Next Fellowship, he plans to further investigate whether stimulating GLS dependent glutamine catabolism is a potential osteoanabolic strategy for bone formation and regeneration in pathological osteoporosis and fracture healing.
Jeongeun Hyun, Ph.D.
Jeongeun received her Ph.D. degree in Integrated Biological Science at the Pusan National University, in South Korea, where she studied post-transcriptional regulation of microRNAs during trans-differentiation of hepatic stellate cells and the therapeutic role of microRNAs in liver fibrosis, under the supervision of Dr. Youngmi Jung. She recently joined the laboratory of Dr. Anna Mae Diehl in the Department of Medicine, where she is investigating the role of RNA-binding proteins as important gene regulators in control of cellular plasticity during adult liver regeneration and in clinically relevant liver disease. As an RNI fellow, she aims to identify the native mechanisms that can be manipulated to improve recovery from liver injury, and specifically by preventing excessive accumulation of myofibroblastic hepatic stellate cells.
Francesco Paolo Ulloa Severino, Ph.D.
Francesco conducted his PhD studies in Neurobiological Sciences at ISAS, Trieste, Italy, under the mentorship of Prof. Vincent Torre. Francesco is fascinated by the mechanisms that nature uses to develop and shape the central nervous system. He wants to investigate the cross-talk between neurons and glial cells that underlies proper brain function. He is also interested in developing and applying advanced imaging and physiological technologies to investigate and repair the nervous system. Francesco will be jointly mentored during his RNI Fellowship by Drs. Cagla Eroglu (Cell biology) and Henry Yin (Neurobiology) to study how manipulation of astrocytic function could help recover motor functionality under disease conditions such as Huntington’s disease
This post originally appeared on Duke Today and is reposted here with permission.
New research from Duke has found that some lung cancer cells with errors in transcription factors begin to resemble their nearest relatives – the cells of the stomach and gut. (Credit – Tata Lab, Duke University)
DURHAM, N.C. – Tumors are notoriously mixed up; cells from one part often express different genes and adopt different sizes and shapes than cells from another part of that same tumor.
Still, a team of researchers were surprised when they recently spotted a miniature stomach, duodenum, and small intestine hidden among the cells of lung tumor samples.
They discovered that these cells had lost a gene called NKX2-1 that acts as a master switch, flipping a network of genes to set the course for a lung cell. Without it, the cells follow the path of their nearest developmental neighbor — the gut — much like a train jumping tracks when a railroad switch fails.
The findings, published March 26 in the journal Developmental Cell, underscore the amazing resilience and plasticity of cancer cells. Such plasticity can presumably enable tumors to develop drug resistance, arguably the biggest challenge to successful cancer treatment.
“Cancer cells will do whatever it takes to survive,” said Purushothama Rao Tata, Ph.D., lead study author and assistant professor of cell biology at Duke University School of Medicine and a member of the Duke Cancer Institute. “Upon treatment with chemotherapy, lung cells shut down some of the key cell regulators and pick up the characteristics of other cells in order to gain resistance.”
Tata has spent most of his career studying the cell types that make up normal lung tissue and how these cells display flexibility during regeneration following an injury. Tata began to wonder whether some of the same rules that he had found governing the normal development and regeneration of tissues might also be responsible for the jumbled nature of tumor cells.
He decided to focus on non-small cell lung cancer, which accounts for 80 to 85 percent of all lung cancer cases. Lung cancer is the leading cause of cancer deaths worldwide, and has one of the lowest survival rates among all cancers. Tata analyzed data from the Cancer Genome Atlas Research Network, a large consortium that has profiled the genomes of thousands of samples from 33 different types of cancer. He found that a large proportion of non-small cell lung cancer tumors lacked NKX2-1, a gene known to specify the lung lineage. Instead, many of them expressed a number of genes associated with esophagus and gastrointestinal organs.
In the absence of NKX2-1, Tata hypothesized, lung tumor cells would lose their lung identity and take on the characteristics of other cells. Because during development lung cells and gut cells are derived from the same parent, or progenitor, cells, it made sense that once the lung cells lost their way they would follow the path of their nearest developmental sibling.
To test whether this was the case, Tata and his colleagues generated different mouse models. First, they knocked out the NKX2-1 gene in the lung tissue of mice. Under the microscope, they noticed features that normally only appear in the gut, such as crypt-like structures and gastric tissues. Amazingly, these structures produced digestive enzymes, as if they resided in the stomach and not the lung.
Having shown that a simple genetic tweak could prompt lung cells to switch developmental tracks, Tata wondered if another tweak or two could fuel them to form tumors. This time, in addition to knocking out NKX2-1, they activated the oncogenes SOX2 or KRAS. The team found that mice with the superimposed SOX2 mutations developed tumors that looked as if they belonged in the foregut; those with KRAS mutations developed tumors that resembled parts of the mid- and hindgut.
Tata and colleagues then wanted to know if these genes were sufficient to alter the fate of lung cells, or if they needed additional signals from their native microenvironment. To answer this question, they developed a novel “mini-lung tumoroid” system — miniaturized versions of lung tumor tissue — and found that manipulation of genetics was enough for the lung cells to show such plasticity.
“Cancer biologists have long suspected that cancer cells could shape shift in order to evade chemotherapy and acquire resistance, but they didn’t know the mechanisms behind such plasticity,” said Tata. “Now that we know what we are dealing with in these tumors – we can think ahead to the possible paths these cells might take and design therapies to block them.”
In the future, Tata plans to use his mini-lung tumoroid system to further explore the mechanisms of resistance in lung cancer cells.
This research was supported by the New York Stem Cell Foundation, the National Institutes of Health/National Heart, Lung, and Blood Institute Early Career Research New Faculty (P30) award (5P30HL101287-02) and RO1 (RO1HL118185), the Harvard Ludwig Cancer Center, the Massachusetts Eye and Ear Infirmary, a Harvard Stem Cell Institute Junior Investigator Grant, an NIH MSTP training grant (T32GM007205), the Medical Scientist Training Program (GM007101), an NIH/NHLBI Career Development Award (K99HL127181), the Whitehead Scholar Program, the Maroni Research Scholar Program, and the HHMI Faculty Scholar Program.
CITATION: “Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity,” Purushothama Rao Tata, Ryan Dz-Wei Chow, Srinivas Vinod Saladi, Aleksandra Tata, Arvind Konkimalla, Anne Bara, Daniel Montoro, Lida P. Hariri, Angela R. Shih, Mari Mino-Kenudson, Hongmei Mou, Sioko Kimura, Leif W. Ellisen, Jayaraj Rajagopal. Developmental Cell, March 26, 2018. DOI: 10.1016/j.devcel.2018.02.024
Dr. Brigid Hogan, Chair, Duke Cell Biology Department
Distinguished developmental biologists from just down the hall and as far away as Singapore, Japan, and England convened at Duke on Friday, March 9, for a special symposium on Developing the Mouse Embryo. Speakers at the symposium highlighted breakthroughs in cell and developmental biology and implications for human health. The day-long event was a celebration of Dr. Brigid Hogan, Chair of Duke University’s department of Cell Biology. Dr. Hogan is a world leader in developmental biology and stem cell research, and in 2002 was the first woman to be appointed as Chair of a basic science department at Duke University.
Ken Poss, Director of Duke’s Regeneration Next Initiative and Professor of Cell Biology, said, “Brigid has shown remarkable leadership for fifteen years as Department Chair. We all appreciate her vision and her support of the field, as well as her groundbreaking work in developmental biology.”
Dr. Richard Behringer, Professor of Genetics at University of Texas’ MD Anderson Cancer, was a presenter at Friday’s symposium. Dr. Behringer wrote a blog post about the Symposium on the Developmental Biology website, The Node. He recounted that many people shared touching “Brigid stories” showing how Dr. Hogan has inspired a generation of biologists. Dr. Behringer’s blog post is reposted below.
Last Friday March 9, a research symposium was held at Duke University in Durham, North Carolina to honor the career and retirement of Professor Brigid Hogan, Chair of the Department of Cell Biology. Current and former Hogan Lab members, colleagues, and friends came from across America, Japan, and the United Kingdom to join in the celebration of a truly remarkable scientist. There were 14 invited speakers, including former students, postdocs, colleagues from Brigid’s days at Vanderbilt University in Nashville, Tennessee, current members of the Department of Cell Biology at Duke, and friends in the mouse development and genetics field. More than 150 participants that included local students and postdoctoral fellows came to hear outstanding research talks. Among the participants, luminaries in the mouse developmental biology field were there to honor Brigid, including Gail Martin, Liz Robertson, Liz Lacy, Frank Costantini, Phil Soriano, Terry Magnuson, Blanche Capel, Kat Hadjantonakis, and Mary Dickinson. The symposium started with surprise videos from friends Fiona Watt (King’s College London) and Jim Smith (Francis Crick Institute), sending their congratulations to Brigid and one from Brigid’s third graduate student, Peter Holland (University of Oxford), praising her skills at inspiring his confidence as a young scientist during his thesis research. The research talks discussed current research, including gene regulatory networks, cutting-edge microscopic imaging, organogenesis, the genetic basis of human disease, novel gene manipulation approaches, embryos on a chip, organ-specific stem cells, high-throughput mouse mutant phenotyping, and tissue regeneration. The talks highlighted the advances in the field of cell and developmental biology and why this area of research is so important for basic knowledge and human health. To learn more about Brigid’s background and motivation to study mouse embryos and organs see her 2015 interview with The Node (http://bit.ly/2DqfZiM).
In addition, to the wonderful science that was presented that day, all of the speakers had a “Brigid story” that they shared with the audience. Many spoke of her drive, curiosity, generosity, patience, and for those who were trained in her lab, the lessons they learned from her. These included ‘don’t talk yourself out of an experiment, sometimes you just have to do it’, ‘be brave’, ‘finish what you start’, ‘speak up and speak out’. My favorite was ‘don’t apologize for being a tall, confident woman’. Everyone praised Brigid’s skills as a mentor. You can read about Brigid’s thoughts on mentoring in a recent interview in Cell Stem Cell – Mentoring the Next Generation (http://bit.ly/2Dk1PiM). Yes, Brigid is “retiring” but she will still be very active. At the end of the symposium, Brigid thanked everyone for attending and participating, especially those who traveled such long distances. She said it brought “a joy to my heart” and was a “day I’ll always remember”.
Blog post by Kara Manke. This article first appeared on the Duke Research Blog, and is reposted here in its entirety.
Our spines begin as a flexible column called the notochord. Over time, cells on the notochord surface divide into alternating segments that go on to form cartilage and vertebrae.
In the womb, our strong spines start as nothing more than a rope of rubbery tissue. As our bodies develop, this flexible cord, called the notochord, morphs into a column of bone and cartilage sturdy enough to hold up our heavy upper bodies.
Graduate student Susan Wopat and her colleagues in Michel Bagnat’s lab at Duke are studying the notochords of the humble zebrafish to learn how this cartilage-like rope grows into a mature spine.
In a new paper, they detail the cellular messaging that directs this transformation.
It all comes down to Notch receptors on the notochord surface, they found. Notch receptors are a special type of protein that sits astride cell membranes. When two cells touch, these Notch receptors link up, forming channels that allow messages to rapidly travel between large groups of cells.
Notch receptors divide the outer notochord cells into two alternating groups – one group is told to grow into bone, while the other is told to grow into cartilage. Over time, bone starts to form on the surface of the notochord and works its way inward, eventually forming mature vertebrae.
When the team tinkered with the Notch signaling on the surface cells, they found that the spinal vertebrae came out deformed – too big, too small, or the wrong shape.
Meddling with cellular signaling on the notochord surface caused zebrafish spines to develop deformities. The first and third image show healthy spines, and the second and fourth image show deformed spines.
“These results demonstrate that the notochord plays a critical role in guiding spine development,” Wopat said. “Further investigation into these findings may help us better understand the origin of spinal defects in humans.”
We are seeking a highly qualified individual with extensive experience in animal surgery and handling. The main research area of our group is regenerative therapies for cardiac injury and disease. The position will be situated in a stimulating environment that provides excellent opportunities for scientific growth in the pursuit of a variety of careers.
•Perform surgical induction of myocardial infarction, transverse aortic constriction in mouse and rat hearts, microinjection into the vasculature and myocardial wall, implantation of a bioengineered cardiac tissue patch on the heart and follow-up physiological and hemodynamic studies including echocardiographic analysis and PV loops.
•Perform pre- and post-operative care and observations.
•Responsibilities may also include interpreting experimental results and guiding lab members through surgical methods and analyses, and to help prepare reports of research for presentation or publication including high-quality figures that convey new findings.
•Bachelors degree in biology, physiology, veterinary medicine, medicine, or other relevant areas of biomedical sciences.
•Technical proficiency and collaborative ability as well as independent thought.
•In-depth knowledge of multiple areas and of the underlying principles and concepts.
•Strong training in small animal surgery, including cardiac injuries.
•Proficient with animal restraint, anesthesia, intubation, and ventilation.
Perform other related duties incidental to the work described herein. The above statements describe the general nature and level of work This is not intended to be an exhaustive list of all responsibilities and duties required of personnel so classified. being performed by individuals assigned to this classification.
Duke University is an Affirmative Action/Equal Opportunity Employer committed to providing employment opportunity without regard to an individual’s age, color, disability, gender, gender expression, gender identity, genetic information, national origin, race, religion, sex, sexual orientation, or veteran status.
This image shows a cross-section of the rat retina. Müller glial cells are shown in green and their reactivity is shown in red. Image credit: Sehwon Koh, Ph.D.
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals aged 60 or older. No effective treatments are currently available for most of these patients, but cell transplantation-based therapies are being developed and tested in clinical trials. A new study by Regeneration Next Postdoctoral Fellow Sehwon Koh, Duke faculty member Cagla Eroglu, and colleagues is shedding light on a possible transplantation-based treatment for AMD and other diseases that cause loss of visual function.
The retina is a complex tissue in the eye that is responsible for visual function. Photoreceptors are one of the types of retinal neurons that turn light entering the eye into nerve signals. Many retinal diseases including AMD affect photoreceptors and cause them to progressively degenerate. Koh, Eroglu, and colleagues show that transplantation of umbilical cord-derived cells into the subretinal region of the eye can preserve visual function by protecting photoreceptors. They also show that the transplanted cells help to preserve neuron-to-neuron connections (synaptic connections) that transmit important information.
Koh and colleagues also examined a different type of retinal cell, the Müller glial cell, which plays an important role in supporting retinal cell health and regulating synaptic connections. The authors found that Müller glial cells become highly reactive even before photoreceptor cell death, and may contribute to cell death. The transplanted umbilical-cord derived cells secrete factors that weaken Müller glial cell reactivity, consequently improving retinal health and synaptic connections. Koh and colleagues show how subretinal transplantation could work to preserve visual function and highlight Müller Glial cells as a potential therapeutic target for the treatment of diseases like macular degeneration.
The paper was published as an early release article in the Journal of Neuroscience and can be accessed here>
An image depicting how neurons transmit chemical information in waves. Image courtesy Victoria Deneke
Ever wonder how your brain can quickly tell your hand to move? Your brain and other systems in biology that have to spread information across large distances use chemical waves to communicate rapidly. Chemical waves are traveling waves that actively transmit biochemical information through a medium. Depicted is a cartoon of a neuron, which is the road that your body uses to send information from your brain to the rest of your body. To the right is a heat map that shows a simulation of a chemical wave traveling through space. Graduate student Victoria Deneke and Dr. Stefano Di Talia highlight the advantages and numerous examples of chemical waves in biology that range from embryogenesis to regeneration in a new review article published in the Journal of Cell Biology. Read the review here >