Time filter

Source Type

News Article | May 8, 2017
Site: www.eurekalert.org

La Jolla, Calif., May 8, 2017 - An international collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP), with major participation from Yokohama School of Medicine, Harvard Medical School, and UC San Diego, has identified the molecular mechanism behind lithium's effectiveness in treating bipolar disorder patients. The study, published in Proceedings of the National Academy of Sciences (PNAS), utilized human induced pluripotent stem cells (hiPS cells) to map lithium's response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. It may also provide the basis to discover new drugs that are safer and more effective than lithium. Bipolar disorder is a mental health condition causing extreme mood swings that include emotional highs (mania or hypomania) and lows (depression) and affects approximately 5.7 million adults in the U.S. Lithium is the first treatment explored after bipolar symptoms, but it has significant limitations. Only approximately one-third of patients respond to lithium treatment, and its effect is only found through a trial-and-error process that takes months--and sometimes years--of prescribing the drug and monitoring for response. Side effects of lithium treatment can be significant, including nausea, muscle tremors, emotional numbing, irregular heartbeat, weight gain, and birth defects, and many patients choose to stop taking the medicine as a result. "Lithium has been used to treat bipolar disorder for generations, but up until now our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks," said Evan Snyder, M.D., Ph.D., professor and director of the Center for Stem Cells and Regenerative Medicine at SBP, and senior author of the study. "Importantly, our findings open a clear path to finding safe and effective new drugs. Equally as important, it helped give us insight into what type of mechanisms cause psychiatric problems such as these." "We realized that studying the lithium response could be used as a 'molecular can-opener' to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene--in this case, CRMP2, an intracellular protein that regulates neural networks," added Snyder. In hiPS cells created from lithium-responsive and non-responsive patients, researchers observed a physiological difference in the regulation of CRMP2, which rendered the protein to be in a much more inactive state in responsive patients. However, the research showed that when lithium was administered to these cells, their regulatory mechanisms were corrected, restoring normal activity of CRMP2 and correcting the underlying cause of their disorder. Thus, the study demonstrated that bipolar disorder can be rooted in physiological--not necessarily genetic--mechanisms. The insights derived from the hiPS cells were validated in actual brain specimens from patients with bipolar disorder (on and off lithium), in animal models, and in the actions of living neurons. "This 'molecular can-opener' approach--using a drug known to have a useful action without exactly knowing why--allowed us to examine and understand an underlying pathogenesis of bipolar disorder," said Snyder. "The approach may be extended to additional complex disorders and diseases for which we don't understand the underlying biology but do have drugs that may have some beneficial actions, such as depression, anxiety, schizophrenia and others in need of more effective therapies. One cannot improve a therapy until one knows what molecularly really needs to be fixed." This study was performed in collaboration with Veterans Administration Medical Center in La Jolla, University of California San Diego, Yokohama City University, Massachusetts General Hospital, Harvard Medical School, Mailman Research Center at McLean Hospital, University of Connecticut School of Medicine, University of Pittsburgh Medical Center, National Institute of Mental Health, Vala Sciences, Inc., Broad Institute of MIT and Harvard University, Dalhousie University, Beth-Israel Deaconess Medical Center, Örebro University, Janssen Research & Development Labs, Waseda University, and RIKEN . Funding was provided by the National Institutes of Health (grants RC2MH090011, R21MH093958, R33MH087896 and R01MH095088 and the Library of Integrated Network-based Cellular Signatures Program), the Viterbi Foundation Neuroscience Initiative, the Stanley Medical Research Institute, the Tau Consortium, the California Institute of Regenerative Medicine, the California Bipolar Foundation and the International Bipolar Foundation. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | December 21, 2016
Site: www.eurekalert.org

Research in the laboratory of Rebecca Wingert, the Gallagher Family Associate Professor of Adult Stem Cell Research in the Department of Biological Sciences at the University of Notre Dame, has confirmed the key role of a certain small molecule in the development of kidney structures in zebrafish, a widely used model for human kidneys. The discovery could help advance understanding to address issues such as birth defects and repair of the kidney after illness or injury. Using an innovative screen approach that graduate student Shahram Jevin Poureetezadi designed, the team exposed zebrafish embryos to small molecules, prostaglandin E2, from a chemical library of such molecules known to be active in cell development generally. The researchers wanted to identify small molecules that regulate or modify development. They discovered that activating or interrupting the prostaglandin pathway has a direct impact on the kidney, meaning that it is essential for normal development. The discovery is the culmination of six years of work in the lab, assembling various genes that are important for making kidney cells. Now that the pieces are being connected and the role of prostaglandin is established, Wingert will turn attention to gaining a deeper molecular and mechanistic understanding of how the molecule works in kidney development, especially the gene targets of the signaling. Prostaglandin E2 regulates the formation of blood stem cells and is known to influence the choice between the formation of the liver or pancreas. Based on the new findings, Wingert speculates that prostaglandin E2 may have critical effects on renal stem cells. In the long term, she expects to investigate whether the pathway has relevance for kidneys' regeneration or failure to regenerate. A paper on the work, "Prostaglandin signaling regulates nephron segment patterning of renal progenitors during zebrafish kidney development," was published in the journal eLife this week. In addition to Wingert, authors include Poureetezadi, Christina N. Cheng, Joseph M. Chambers and Bridgette E. Drummond, graduate students in her laboratory, the Center for Stem Cells and Regenerative Medicine and the Center for Zebrafish Research.


News Article | February 15, 2017
Site: www.cemag.us

Scientists are one step closer to mimicking the way biological systems interact and process information in the body — a vital step toward developing new forms of biorobotics and novel treatment approaches for several muscle-related health problems such as muscular degenerative disorders, arrhythmia, and limb loss. Using cardiac muscle cells and cardiac fibroblasts — cells found in connective heart tissue – researchers at the University of Notre Dame have created a “living diode,” which can be used for cell-based information processing, according to a recent study in Advanced Biosystems. Bioengineers created the muscle-based circuitry through a novel, self-forming, micro patterning approach. Using muscle cells opens the door to functional, biological structures or “computational tissues” that would allow an organ to control and direct mechanical devices in the body. The design arranges the two types of cells in a rectangular pattern, separating excitable cells from nonexcitable cells, allowing the team to transduce electrical signals unidirectionally and achieve a diode function using living cells. In addition to the diode-like function, the natural pacing ability of the muscle cells allowed Pinar Zorlutuna, assistant professor of aerospace and mechanical engineering, and her team to pass along information embedded in the electrical signals by modulating the frequency of the cells’ electrical activity. Zorlutuna’s research was funded by the National Science Foundation. “Muscle cells have the unique ability to respond to external signals while being connected to fibroblasts internally through intercellular junctions. By combining these two cell types, we have the ability to initiate, amplify and propagate signals directionally,” says Zorlutuna, who is also director of the Tissue Engineering Laboratory at the university. “The success of these muscle-cell diodes offers a path toward linking such cell-based circuitry to a living system — and creating functional control units for biomedical engineering applications such as bioactuators or biosensors.” The team’s work presents a new option in biocomputing, which has focused primarily on using gene circuitries of genetically modified single-cells or neuronal networks doped with chemical additives to create information processing systems. The single-cell options are slower to process information since they rely on chemical processes, and neuronal-based approaches can misfire signals, firing backward up to 10 percent of the time. Zorlutuna explores biomimetic environments in order to understand and control cell behavior. She also studies cell-cell and cell-environment interactions through tissue and genetic engineering, and micro- and nanotechnology at the Notre Dame Center for Nano Science and Technology. She is a researcher at the University’s Center for Stem Cells and Regenerative Medicine and the Harper Cancer Research Institute.


News Article | February 15, 2017
Site: phys.org

Using cardiac muscle cells and cardiac fibroblasts - cells found in connective heart tissue - researchers at the University of Notre Dame have created a "living diode," which can be used for cell-based information processing, according to a recent study in Advanced Biosystems. Bioengineers created the muscle-based circuitry through a novel, self-forming, micro patterning approach. Using muscle cells opens the door to functional, biological structures or "computational tissues" that would allow an organ to control and direct mechanical devices in the body. The design arranges the two types of cells in a rectangular pattern, separating excitable cells from nonexcitable cells, allowing the team to transduce electrical signals unidirectionally and achieve a diode function using living cells. In addition to the diode-like function, the natural pacing ability of the muscle cells allowed Pinar Zorlutuna, assistant professor of aerospace and mechanical engineering, and her team to pass along information embedded in the electrical signals by modulating the frequency of the cells' electrical activity. Zorlutuna's research was funded by the National Science Foundation. "Muscle cells have the unique ability to respond to external signals while being connected to fibroblasts internally through intercellular junctions. By combining these two cell types, we have the ability to initiate, amplify and propagate signals directionally," said Zorlutuna, who is also director of the Tissue Engineering Laboratory at the university. "The success of these muscle-cell diodes offers a path toward linking such cell-based circuitry to a living system - and creating functional control units for biomedical engineering applications such as bioactuators or biosensors." The team's work presents a new option in biocomputing, which has focused primarily on using gene circuitries of genetically modified single-cells or neuronal networks doped with chemical additives to create information processing systems. The single-cell options are slower to process information since they relay on chemical processes, and neuronal-based approaches can misfire signals, firing backward up to 10 percent of the time. Zorlutuna explores biomimetic environments in order to understand and control cell behavior. She also studies cell-cell and cell-environment interactions through tissue and genetic engineering, and micro- and nanotechnology at the Notre Dame Center for Nano Science and Technology. She is a researcher at the University's Center for Stem Cells and Regenerative Medicine and the Harper Cancer Research Institute. Explore further: Researchers use stem cells to regenerate the external layer of a human heart More information: Uryan Isik Can et al. Muscle-Cell-Based "Living Diodes", Advanced Biosystems (2017). DOI: 10.1002/adbi.201600035


News Article | February 15, 2017
Site: www.eurekalert.org

Scientists are one step closer to mimicking the way biological systems interact and process information in the body - a vital step toward developing new forms of biorobotics and novel treatment approaches for several muscle-related health problems such as muscular degenerative disorders, arrhythmia and limb loss. Using cardiac muscle cells and cardiac fibroblasts - cells found in connective heart tissue - researchers at the University of Notre Dame have created a "living diode," which can be used for cell-based information processing, according to a recent study in Advanced Biosystems. Bioengineers created the muscle-based circuitry through a novel, self-forming, micro patterning approach. Using muscle cells opens the door to functional, biological structures or "computational tissues" that would allow an organ to control and direct mechanical devices in the body. The design arranges the two types of cells in a rectangular pattern, separating excitable cells from nonexcitable cells, allowing the team to transduce electrical signals unidirectionally and achieve a diode function using living cells. In addition to the diode-like function, the natural pacing ability of the muscle cells allowed Pinar Zorlutuna, assistant professor of aerospace and mechanical engineering, and her team to pass along information embedded in the electrical signals by modulating the frequency of the cells' electrical activity. Zorlutuna's research was funded by the National Science Foundation. "Muscle cells have the unique ability to respond to external signals while being connected to fibroblasts internally through intercellular junctions. By combining these two cell types, we have the ability to initiate, amplify and propagate signals directionally," said Zorlutuna, who is also director of the Tissue Engineering Laboratory at the university. "The success of these muscle-cell diodes offers a path toward linking such cell-based circuitry to a living system - and creating functional control units for biomedical engineering applications such as bioactuators or biosensors." The team's work presents a new option in biocomputing, which has focused primarily on using gene circuitries of genetically modified single-cells or neuronal networks doped with chemical additives to create information processing systems. The single-cell options are slower to process information since they relay on chemical processes, and neuronal-based approaches can misfire signals, firing backward up to 10 percent of the time. Zorlutuna explores biomimetic environments in order to understand and control cell behavior. She also studies cell-cell and cell-environment interactions through tissue and genetic engineering, and micro- and nanotechnology at the Notre Dame Center for Nano Science and Technology. She is a researcher at the University's Center for Stem Cells and Regenerative Medicine and the Harper Cancer Research Institute.


Tzameret A.,Tel Aviv University | Sher I.,Tel Aviv University | Belkin M.,Tel Aviv University | Treves A.J.,Center for Stem Cells and Regenerative Medicine | And 6 more authors.
Experimental Eye Research | Year: 2014

Vision incapacitation and blindness associated with retinal degeneration affect millions of people worldwide. Cell based therapy and specifically transplantation of human adult bone marrow-derived stem cells (hBM-MSCs) present possible treatment strategy. Subretinal transplantation of human or rat BM-MSCs was shown previously to improve retinal function in Royal College Surgeons (RCS) rats. In those studies cells were transplanted via a transscleral-transchoroidal approach, creating a localized subretinal bleb. Limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection site. Here we describe a new surgical method for subretinal transplantation that facilitates uniform distribution of transplanted cells as a thin layer along most of the subretinal space. We assessed the therapeutic effect of hBM-MSCs on RCS rats when transplanted either subretinally or intravitreally. We also examined whether a second transplantation can prolong the therapeutic effect. A cell suspension of 2.5×106 cells in 5μl was injected subretinally or intravitreally in RCS rats at 28 days postnatal. In the subretinal group, hBM-MSCs were transplanted posterior to the limbus in the superotemporal part of the eye through a longitudinal triangular scleral tunnel reaching the choroid. In the intravitreal group, the cells were injected into the superotemporal part of the vitreous cavity. In cross sections of subretinally transplanted eyes, removed 2h following transplantation, hBM-MSCs were distributed as a near-homogenous thin layer along most of the subretinal space. In some animals the cells were also detected in the choroid. In the intravitreal injection group, hBM-MSCs were clustered in the vitreous cavity. Transplanted cells could be detected up to 2 weeks after transplantation but not at later time points. Retinal function and structure were assessed by electroretinogram (ERG) and histology analysis, respectively. Six weeks post transplantation, the mean maximal scotopic ERG b-wave amplitude response recorded in RCS control eyes was 1.2μV. By contrast, in transplanted eyes mean responses of 56.4μV and 66.2μV were recorded in the intravitreally and subretinally transplanted eyes, respectively. In the subretinal group, retinal function was significantly higher in transplanted compared with control eyes up to 20 weeks following transplantation. By contrast, in the intravitreal group, rescue of retinal function persisted only up to 12 weeks following transplantation. Histological analysis revealed that 8 weeks following subretinal transplantation, the retinas of control eyes were dystrophic, with outer nuclear layer (ONL) containing a single cell layer. An extensive photoreceptor rescue was demonstrated in transplanted eyes at this time point, with 3-4 cell layers in the ONL along the entire retina. A second subretinal transplantation at 70 days postnatal did not enhance or prolong the therapeutic effect of hBM-MSCs. No immunosuppressants were used and long-term safety analysis demonstrated no gross or microscopic adverse effects. Taken together our findings suggest that transplantation of hBM-MSCs as a thin subretinal layer enhances the therapeutic effect and the safety of cell transplantation. © 2013 Elsevier Ltd.


Tzameret A.,Tel Aviv University | Sher I.,Tel Aviv University | Belkin M.,Tel Aviv University | Treves A.J.,Center for Stem Cells and Regenerative Medicine | And 5 more authors.
Stem Cell Research | Year: 2015

Vision incapacitation and blindness associated with incurable retinal degeneration affect millions of people worldwide. In this study, 0.25×106 human bone marrow stem cells (hBM-MSCs) were transplanted epiretinally in the right eye of Royal College Surgeons (RCS) rats at the age of 28 days. Epiretinally transplanted cells were identified as a thin layer of cells along vitreous cavity, in close proximity to the retina or attached to the lens capsule, up to 6 weeks following transplantation. Epiretinal transplantation delayed photoreceptor degeneration and rescued retinal function up to 20 weeks following cell transplantation. Visual functions remained close to normal levels in epiretinal transplantation rats. No inflammation or any other adverse effects were observed in transplanted eyes.Our findings suggest that transplantation of hBM-MSCs as a thin epiretinal layer is effective for treatment of retinal degeneration in RCS rats, and that transplanting the cells in close proximity to the retina enhances hBM-MSC therapeutic effect compared with intravitreal injection. © 2015.


PubMed | Center for Stem Cells and Regenerative Medicine, Tel Aviv University and Sheba Medical Center
Type: Journal Article | Journal: Stem cell research | Year: 2015

Vision incapacitation and blindness associated with incurable retinal degeneration affect millions of people worldwide. In this study, 0.2510(6) human bone marrow stem cells (hBM-MSCs) were transplanted epiretinally in the right eye of Royal College Surgeons (RCS) rats at the age of 28 days. Epiretinally transplanted cells were identified as a thin layer of cells along vitreous cavity, in close proximity to the retina or attached to the lens capsule, up to 6 weeks following transplantation. Epiretinal transplantation delayed photoreceptor degeneration and rescued retinal function up to 20 weeks following cell transplantation. Visual functions remained close to normal levels in epiretinal transplantation rats. No inflammation or any other adverse effects were observed in transplanted eyes. Our findings suggest that transplantation of hBM-MSCs as a thin epiretinal layer is effective for treatment of retinal degeneration in RCS rats, and that transplanting the cells in close proximity to the retina enhances hBM-MSC therapeutic effect compared with intravitreal injection.


PubMed | Center for Stem Cells and Regenerative Medicine, Tel Aviv University and Sheba Medical Center
Type: | Journal: Experimental eye research | Year: 2013

Vision incapacitation and blindness associated with retinal degeneration affect millions of people worldwide. Cell based therapy and specifically transplantation of human adult bone marrow-derived stem cells (hBM-MSCs) present possible treatment strategy. Subretinal transplantation of human or rat BM-MSCs was shown previously to improve retinal function in Royal College Surgeons (RCS) rats. In those studies cells were transplanted via a transscleral-transchoroidal approach, creating a localized subretinal bleb. Limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection site. Here we describe a new surgical method for subretinal transplantation that facilitates uniform distribution of transplanted cells as a thin layer along most of the subretinal space. We assessed the therapeutic effect of hBM-MSCs on RCS rats when transplanted either subretinally or intravitreally. We also examined whether a second transplantation can prolong the therapeutic effect. A cell suspension of 2.510(6) cells in 5l was injected subretinally or intravitreally in RCS rats at 28 days postnatal. In the subretinal group, hBM-MSCs were transplanted posterior to the limbus in the superotemporal part of the eye through a longitudinal triangular scleral tunnel reaching the choroid. In the intravitreal group, the cells were injected into the superotemporal part of the vitreous cavity. In cross sections of subretinally transplanted eyes, removed 2h following transplantation, hBM-MSCs were distributed as a near-homogenous thin layer along most of the subretinal space. In some animals the cells were also detected in the choroid. In the intravitreal injection group, hBM-MSCs were clustered in the vitreous cavity. Transplanted cells could be detected up to 2 weeks after transplantation but not at later time points. Retinal function and structure were assessed by electroretinogram (ERG) and histology analysis, respectively. Six weeks post transplantation, the mean maximal scotopic ERG b-wave amplitude response recorded in RCS control eyes was 1.2V. By contrast, in transplanted eyes mean responses of 56.4V and 66.2V were recorded in the intravitreally and subretinally transplanted eyes, respectively. In the subretinal group, retinal function was significantly higher in transplanted compared with control eyes up to 20 weeks following transplantation. By contrast, in the intravitreal group, rescue of retinal function persisted only up to 12 weeks following transplantation. Histological analysis revealed that 8 weeks following subretinal transplantation, the retinas of control eyes were dystrophic, with outer nuclear layer (ONL) containing a single cell layer. An extensive photoreceptor rescue was demonstrated in transplanted eyes at this time point, with 3-4 cell layers in the ONL along the entire retina. A second subretinal transplantation at 70 days postnatal did not enhance or prolong the therapeutic effect of hBM-MSCs. No immunosuppressants were used and long-term safety analysis demonstrated no gross or microscopic adverse effects. Taken together our findings suggest that transplantation of hBM-MSCs as a thin subretinal layer enhances the therapeutic effect and the safety of cell transplantation.

Loading Center for Stem Cells and Regenerative Medicine collaborators
Loading Center for Stem Cells and Regenerative Medicine collaborators