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News Article | December 21, 2016
Site: www.chromatographytechniques.com

In a first-in-children randomized clinical study, medical researchers at the University of Maryland School of Medicine (UM SOM) and the Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami Miller School of Medicine have begun testing to see whether adult stem cells derived from bone marrow benefit children with the congenital heart defect hypoplastic left heart syndrome (HLHS). UM SOM surgeons are injecting the cells into the babies’ hearts during open-heart operations at the University of Maryland Medical Center. ISCI is supplying the stem cells for the procedures. Even with extensive surgical treatments, HLHS babies still do not have optimal outcomes. The researchers hope the cells will increase the babies’ chances of survival as HLHS limits the heart's ability to pump blood from the heart to the body. “The premise of this clinical trial is to boost or regenerate the right ventricle, the only ventricle in these babies, to make it pump as strongly as a normal left ventricle,” says lead researcher Sunjay Kaushal, MD, PhD, associate professor of surgery, University of Maryland School of Medicine and director, pediatric cardiac surgery, University of Maryland Medical Center. “We are hoping this therapy will be a game-changer for these patients.” Kaushal says the first two patients, who were both four-months-old when the stem cells were injected, are doing well after their surgery. This is the first HLHS research in the United States to use stem cells known as allogeneic mesenchymal stem cells (MSC). Allogeneic cells can be used in other human beings without creating an immune response, which could cause the body to reject the cells. Additionally, these cells are a type of adult stem cell (found in both children and adults), unspecialized cells that can develop into tissue- or organ-specific cells. MSCs can be harvested in advance, expanded in culture, and stored for use later. The allogeneic nature of the MSCs makes it possible for stem cells from one bone marrow donor to provide all the stem cells for this study. Researchers elsewhere are taking a different approach to strengthen the HLHS heart, with autologous cells, stem cells taken from the HLHS patient's own umbilical cord, for use in that specific patient. In adult patients, MSCs in the heart have been shown to reduce scar tissue, reduce inflammation, cause new small vessels to grow, and stimulate the heart to regenerate itself, causing heart muscle cells and cardiac stem cells to grow. "We've had incredible results in using mesenchymal stem cells to regenerate damaged heart muscle in adults," says Joshua M. Hare, MD, ISCI founding director and sponsor of the study. “This is the first time these types of cells are being used in infants, so this is very exciting.” The Interdisciplinary Stem Cell Institute has grown from a local research center to a national cell manufacturing facility. ISCI provides cells for the Cardiovascular Cell Therapy Research Network, has been named a Production Assistance for Cellular Therapies Center by the National Heart, Lung and Blood Institute, and has been conducting research in stem cell use for cardiovascular repair since 2008. HLHS is one of the most challenging and complex congenital heart diseases to treat. The Centers for Disease Control and Prevention (CDC) estimates that about 960 babies in the United States are born each year with HLHS. For unknown reasons, the heart’s main pumping chamber, the left ventricle, does not develop completely during a critical growth period just prior to birth. The right ventricle normally pumps blood to the lungs at low pressure to be oxygenated, while the left ventricle pushes blood at high pressure through the aorta to the entire body. In children with HLHS, the right heart assumes the extra workload, temporarily supporting the circulation to both the lungs and body. That stress can cause the right heart to fail and the baby to die. Current HLHS treatment options are either a heart transplant or a series of three open-heart reconstructive surgical procedures to connect the left and right sides of the heart. However, even with a transplant or the reconstructive surgical series, children with HLHS have an average five-year survival of only 50 to 60 percent. In this Phase 1 safety and efficacy study, allogeneic MSCs are injected into the heart muscle during the second of the three reconstructive surgeries, typically performed at approximately four months of age. A total of 30 patients with HLHS will be enrolled in the study. Fifteen patients will receive six-to-eight stem cell injections each, based on the size of the heart, while 15 control patients will not receive the cells. This is an open-label trial, in which researchers and participant families will know whether or not the cells are administered. Kaushal laid the groundwork for this trial eight years ago as he began exploring the possibilities of stem cells to strengthen children’s hearts. Kaushal says he and his team developed many models trying to understand how these cells work in the laboratory before moving to a clinical application. “There’s a lot of basic science behind what we’re doing. I want to make sure that what we pursue is rigorous in the laboratory, to make sure that we’re providing the best therapy for these little kids.” Several researchers at the School of Medicine’s University of Maryland Center for Stem Cell Biology & Regenerative Medicine have added their expertise to the effort, collaborating with Dr. Kaushal to understand and develop stem cell therapy for children with heart failure. “Dr. Kaushal and colleagues have discovered that the failing neonatal heart is actually a rich source of cardiac stem cells, but the existing stem cells in the hearts of these babies are not sufficient to overcome HLHS,” says Curt I. Civin, MD, professor of pediatrics and physiology, director of the Center for Stem Cell Biology & Regenerative Medicine, and Associate Dean for Research at the University of Maryland School of Medicine. “We are close to understanding one mechanism underlying this insufficiency. This line of research is a key part of our quest to use stem cells to repair, cure and prevent severe diseases in children and adults.” In previously published research, Kaushal demonstrated that mesenchymal stem cells can restore function in a pre-clinical model replicating many of the features of HLHS. The stem cells remodeled the heart muscle (myocardium) similar to normal myocardium. Stem cells in the heart may also secrete growth factors conducive to forming heart muscle and keeping the muscle from dying. “These key findings suggested these cells would work for HLHS patients,” says Kaushal. While stem cells have been used to regenerate adult hearts, Kaushal says improvements have been marginal. His research suggests results may be better in pediatric hearts: “The heart is able to remodel better in a younger patient than an older patient, because the body is still growing, good things are going on, and things are not deteriorating.” Civin, a pediatric oncologist, says his very first patient as a pediatric intern-in-training years ago was an infant with HLHS. “I’ve seen how devastating HLHS can be for babies and their families. I’m thrilled with the launch of this first-in-children stem cell therapeutic trial, and look forward to the patient outcomes.” The Department of Surgery at the University of Maryland School of Medicine is providing funding for the clinical costs associated with this trial.


News Article | December 20, 2016
Site: www.eurekalert.org

Baltimore, MD - Dec. 20, 2016 - In a first-in-children randomized clinical study, medical researchers at the University of Maryland School of Medicine (UM SOM) and the Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami Miller School of Medicine have begun testing to see whether adult stem cells derived from bone marrow benefit children with the congenital heart defect hypoplastic left heart syndrome (HLHS). UM SOM surgeons are injecting the cells into the babies' hearts during open-heart operations at the University of Maryland Medical Center. ISCI is supplying the stem cells for the procedures. Even with extensive surgical treatments, HLHS babies still do not have optimal outcomes. The researchers hope the cells will increase the babies' chances of survival as HLHS limits the heart's ability to pump blood from the heart to the body. "The premise of this clinical trial is to boost or regenerate the right ventricle, the only ventricle in these babies, to make it pump as strongly as a normal left ventricle," says lead researcher Sunjay Kaushal, MD, PhD, associate professor of surgery, University of Maryland School of Medicine and director, pediatric cardiac surgery, University of Maryland Medical Center. "We are hoping this therapy will be a game-changer for these patients." Kaushal says the first two patients, who were both four-months-old when the stem cells were injected, are doing well after their surgery. This is the first HLHS research in the United States to use stem cells known as allogeneic mesenchymal stem cells (MSC). Allogeneic cells can be used in other human beings without creating an immune response, which could cause the body to reject the cells. Additionally, these cells are a type of adult stem cell (found in both children and adults), unspecialized cells that can develop into tissue- or organ-specific cells. MSCs can be harvested in advance, expanded in culture, and stored for use later. The allogeneic nature of the MSCs makes it possible for stem cells from one bone marrow donor to provide all the stem cells for this study. Researchers elsewhere are taking a different approach to strengthen the HLHS heart, with autologous cells, stem cells taken from the HLHS patient's own umbilical cord, for use in that specific patient. In adult patients, MSCs in the heart have been shown to reduce scar tissue, reduce inflammation, cause new small vessels to grow, and stimulate the heart to regenerate itself, causing heart muscle cells and cardiac stem cells to grow. "We've had incredible results in using mesenchymal stem cells to regenerate damaged heart muscle in adults," says Joshua M. Hare, MD, ISCI founding director and sponsor of the study. "This is the first time these types of cells are being used in infants, so this is very exciting." The Interdisciplinary Stem Cell Institute has grown from a local research center to a national cell manufacturing facility. ISCI provides cells for the Cardiovascular Cell Therapy Research Network, has been named a Production Assistance for Cellular Therapies Center by the National Heart, Lung and Blood Institute, and has been conducting research in stem cell use for cardiovascular repair since 2008. HLHS is one of the most challenging and complex congenital heart diseases to treat. The Centers for Disease Control and Prevention (CDC) estimates that about 960 babies in the United States are born each year with HLHS. For unknown reasons, the heart's main pumping chamber, the left ventricle, does not develop completely during a critical growth period just prior to birth. The right ventricle normally pumps blood to the lungs at low pressure to be oxygenated, while the left ventricle pushes blood at high pressure through the aorta to the entire body. In children with HLHS, the right heart assumes the extra workload, temporarily supporting the circulation to both the lungs and body. That stress can cause the right heart to fail and the baby to die. Current HLHS treatment options are either a heart transplant or a series of three open-heart reconstructive surgical procedures to connect the left and right sides of the heart. However, even with a transplant or the reconstructive surgical series, children with HLHS have an average five-year survival of only 50-60 percent. In this Phase 1 safety and efficacy study, allogeneic MSCs are injected into the heart muscle during the second of the three reconstructive surgeries, typically performed at approximately four months of age. A total of 30 patients with HLHS will be enrolled in the study. Fifteen patients will receive six-to-eight stem cell injections each, based on the size of the heart, while 15 control patients will not receive the cells. This is an open-label trial, in which researchers and participant families will know whether or not the cells are administered. Kaushal laid the groundwork for this trial eight years ago as he began exploring the possibilities of stem cells to strengthen children's hearts. Kaushal says he and his team developed many models trying to understand how these cells work in the laboratory before moving to a clinical application. "There's a lot of basic science behind what we're doing. I want to make sure that what we pursue is rigorous in the laboratory, to make sure that we're providing the best therapy for these little kids." Several researchers at the School of Medicine's University of Maryland Center for Stem Cell Biology & Regenerative Medicine have added their expertise to the effort, collaborating with Dr. Kaushal to understand and develop stem cell therapy for children with heart failure. "Dr. Kaushal and colleagues have discovered that the failing neonatal heart is actually a rich source of cardiac stem cells, but the existing stem cells in the hearts of these babies are not sufficient to overcome HLHS," says Curt I. Civin, MD, professor of pediatrics and physiology, director of the Center for Stem Cell Biology & Regenerative Medicine, and Associate Dean for Research at the University of Maryland School of Medicine. "We are close to understanding one mechanism underlying this insufficiency. This line of research is a key part of our quest to use stem cells to repair, cure and prevent severe diseases in children and adults." In previously published research, Kaushal demonstrated that mesenchymal stem cells can restore function in a pre-clinical model replicating many of the features of HLHS. The stem cells remodeled the heart muscle (myocardium) similar to normal myocardium. Stem cells in the heart may also secrete growth factors conducive to forming heart muscle and keeping the muscle from dying. "These key findings suggested these cells would work for HLHS patients," says Kaushal. While stem cells have been used to regenerate adult hearts, Kaushal says improvements have been marginal. His research suggests results may be better in pediatric hearts: "The heart is able to remodel better in a younger patient than an older patient, because the body is still growing, good things are going on, and things are not deteriorating." Civin, a pediatric oncologist, says his very first patient as a pediatric intern-in-training years ago was an infant with HLHS. "I've seen how devastating HLHS can be for babies and their families. I'm thrilled with the launch of this first-in-children stem cell therapeutic trial, and look forward to the patient outcomes." The Department of Surgery at the University of Maryland School of Medicine is providing funding for the clinical costs associated with this trial. "Dr. Kaushal's research will give families with a devastating diagnosis hope for a better outcome for their child," says Stephen T. Bartlett, MD, the Peter Angelos Distinguished Professor; Chair of the Department of Surgery at the University of Maryland School of Medicine; and Surgeon-in-Chief and Executive Vice President of the University of Maryland Medical System. "The Department of Surgery's funding of this project demonstrates the critical need and the promise this research holds for a very at-risk population who only have a 50/50 shot at survival with current treatment protocols." "This novel therapeutic approach exemplifies how our faculty are unrelenting in their search for new ways to improve the health of some of our tiniest and most vulnerable patients," says E. Albert Reece, MD, PhD, MBA, vice president for medical affairs, University of Maryland; the John Z. and Akiko K. Bowers Distinguished Professor; and dean, University of Maryland School of Medicine." This stem cell therapy may provide a new treatment option not just for patients with HLHS, but also for patients with other congenital heart problems." For more details on this study, see identifier NCT02398604 on clinicaltrials.gov. About the University of Maryland School of Medicine The University of Maryland School of Medicine was chartered in 1807 and is the first public medical school in the United States. It continues today as an innovative leader in accelerating innovation and discovery in medicine. The School of Medicine is the founding school of the University of Maryland and is an integral part of the 11-campus University System of Maryland. Located on the University of Maryland's Baltimore campus, the School of Medicine works closely with the University of Maryland Medical Center and Medical System to provide a research-intensive, academic and clinically based education. With 43 academic departments, centers and institutes and a faculty of more than 3,000 physicians and research scientists plus more than $400 million in extramural funding, the School is regarded as one of the leading biomedical research institutions in the U.S. with top-tier faculty and programs in cancer, brain science, surgery and transplantation, trauma and emergency medicine, vaccine development and human genomics, among other centers of excellence. The School is not only concerned with the health of the citizens of Maryland and the nation, but also has a global presence, with research and treatment facilities in more than 35 countries around the world. http://medschool. . About the University of Maryland Medical Center The University of Maryland Medical Center (UMMC) is comprised of two hospitals in Baltimore: an 800-bed teaching hospital - the flagship institution of the 12-hospital University of Maryland Medical System (UMMS) - and a 200-bed community teaching hospital, UMMC Midtown Campus. UMMC is a national and regional referral center for trauma, cancer care, neurocare, cardiac care, diabetes and endocrinology, women's and children's health, and has one of the largest solid organ transplant programs in the country. All physicians on staff at the flagship hospital are faculty physicians of the University of Maryland School of Medicine. At UMMC Midtown Campus, faculty physicians work alongside community physicians to provide patients with the highest quality care. UMMC Midtown Campus was founded in 1881 and is located one mile away from the University Campus hospital. For more information, visit http://www. .


Serup P.,Hagedorn Research Institute | Serup P.,Copenhagen University | Gustavsen C.,Hagedorn Research Institute | Gustavsen C.,Copenhagen University | And 16 more authors.
DMM Disease Models and Mechanisms | Year: 2012

Extracellular signals in development, physiology, homeostasis and disease often act by regulating transcription. Herein we describe a general method and specific resources for determining where and when such signaling occurs in live animals and for systematically comparing the timing and extent of different signals in different cellular contexts. We used recombinase-mediated cassette exchange (RMCE) to test the effect of successively deleting conserved genomic regions of the ubiquitously active Rosa26 promoter and substituting the deleted regions for regulatory sequences that respond to diverse extracellular signals. We thereby created an allelic series of embryonic stem cells and mice, each containing a signal-responsive sentinel with different fluorescent reporters that respond with sensitivity and specificity to retinoic acids, bone morphogenic proteins, activin A, Wnts or Notch, and that can be adapted to any pathway that acts via DNA elements.


Calder E.L.,Center for Stem Cell Biology | Calder E.L.,Sloan Kettering Institute | Calder E.L.,Cornell University | Tchieu J.,Center for Stem Cell Biology | And 17 more authors.
Journal of Neuroscience | Year: 2015

The derivation of somatic motoneurons (MNs) from ES cells (ESCs) after exposure to sonic hedgehog (SHH) and retinoic acid (RA) is one of the best defined, directed differentiation strategies to specify fate in pluripotent lineages. In mouse ESCs,MNyield is particularly high after RA + SHH treatment, whereas human ESC (hESC) protocols have been generally less efficient. In an effort to optimize yield, we observe that functional MNs can be derived from hESCs at high efficiencies if treated with patterning molecules at very early differentiation steps before neural induction. Remarkably, under these conditions, equal numbers of human MNs were obtained in the presence or absence of SHH exposure. Using pharmacological and genetic strategies, we demonstrate that early RA treatment directsMNdifferentiation independently of extrinsicSHHactivation by suppressing the induction of GLI3.We further demonstrate that neural induction triggers a switch from a poised to an active chromatin state at GLI3. Early RA treatment prevents this switch by direct binding of the RA receptor at the GLI3 promoter. Furthermore, GLI3 knock-out hESCs can bypass the requirement for early RA patterning to yield MNs efficiently. Our data demonstrate that RAmediated suppression of GLI3 is sufficient to generate MNs in an SHH-independent manner and that temporal changes in exposure to patterning factors such as RA affect chromatin state and competency of hESC-derived lineages to adopt specific neuronal fates. Finally, our work presents a streamlined platform for the highly efficient derivation of human MNs from ESCs and induced pluripotent stem cells. © 2015 the authors.


Fattahi F.,Center for Stem Cell Biology | Fattahi F.,Sloan Kettering Institute for Cancer Research | Fattahi F.,Cornell University | Steinbeck J.A.,Center for Stem Cell Biology | And 23 more authors.
Nature | Year: 2016

The enteric nervous system (ENS) is the largest component of the autonomic nervous system, with neuron numbers surpassing those present in the spinal cord. The ENS has been called the 'second brain' given its autonomy, remarkable neurotransmitter diversity and complex cytoarchitecture. Defects in ENS development are responsible for many human disorders including Hirschsprung disease (HSCR). HSCR is caused by the developmental failure of ENS progenitors to migrate into the gastrointestinal tract, particularly the distal colon. Human ENS development remains poorly understood owing to the lack of an easily accessible model system. Here we demonstrate the efficient derivation and isolation of ENS progenitors from human pluripotent stem (PS) cells, and their further differentiation into functional enteric neurons. ENS precursors derived in vitro are capable of targeted migration in the developing chick embryo and extensive colonization of the adult mouse colon. The in vivo engraftment and migration of human PS-cell-derived ENS precursors rescue disease-related mortality in HSCR mice (Ednrbs-l/s-l), although the mechanism of action remains unclear. Finally, EDNRB-null mutant ENS precursors enable modelling of HSCR-related migration defects, and the identification of pepstatin A as a candidate therapeutic target. Our study establishes the first, to our knowledge, human PS-cell-based platform for the study of human ENS development, and presents cell- and drug-based strategies for the treatment of HSCR. © 2016 Macmillan Publishers Limited. All rights reserved.


Battista D.,Center for Stem Cell Biology | Battista D.,Sloan Kettering Institute for Cancer Research | Ganat Y.,Center for Stem Cell Biology | Ganat Y.,Sloan Kettering Institute for Cancer Research | And 4 more authors.
Stem Cells Translational Medicine | Year: 2014

There has been considerable progress in obtaining engraftable embryonic stem (ES) cell-derived midbrain dopamine neurons for cell replacement therapy in models of Parkinson's disease; however, limited integration and striatal reinnervation of ES-derived grafts remain a major challenge for future clinical translation. In this paper, we show that enhanced expression of polysialic acid results in improved graft efficiency in correcting behavioral deficits in Parkinsonian mice. This result is accompanied by two potentially relevant cellular changes: greater survival of transplanted ES-derived dopamine neurons and robust sprouting of tyrosine hydroxylase-positive processes into host tissue. Because the procedures used to enhance polysialic acid are easily translated to other cell types and species, this approach may represent a general strategy to improve graft integration in cell-based therapies. © AlphaMed Press 2014.


Boulbes D.,University of Texas M. D. Anderson Cancer Center | Chen C.-H.,University of Texas M. D. Anderson Cancer Center | Shaikenov T.,University of Texas M. D. Anderson Cancer Center | Agarwal N.K.,University of Texas M. D. Anderson Cancer Center | And 10 more authors.
Molecular Cancer Research | Year: 2010

In animal cells, growth factors coordinate cell proliferation and survival by regulating the phosphoinositide 3-kinase/Akt signaling pathway. Deregulation of this signaling pathway is common in a variety of human cancers. The PI3K-dependent signaling kinase complex defined as mammalian target of rapamycin complex 2 (mTORC2) functions as a regulatory Ser-473 kinase of Akt. We find that activation of mTORC2 by growth factor signaling is linked to the specific phosphorylation of its component rictor on Thr-1135. The phosphorylation of this site is induced by the growth factor stimulation and expression of the oncogenic forms of ras or PI3K. Rictor phosphorylation is sensitive to the inhibition of PI3K, mTOR, or expression of integrin-linked kinase. The substitution of wild-type rictor with its specific phospho-mutants in rictor null mouse embryonic fibroblasts did not alter the growth factor-dependent phosphorylation of Akt, indicating that the rictor Thr-1135 phosphorylation is not critical in the regulation of the mTORC2 kinase activity. We found that this rictor phosphorylation takes place in the mTORC2-deficient cells, suggesting that this modification might play a role in the regulation of not only mTORC2 but also the mTORC2-independent function of rictor. ©2010 AACR.


Perna F.,Molecular Pharmacology and Chemistry Program | Vu L.P.,Molecular Pharmacology and Chemistry Program | Themeli M.,Molecular Pharmacology and Chemistry Program | Kriks S.,Center for Stem Cell Biology | And 9 more authors.
Stem Cell Reports | Year: 2015

Epigenetic regulation of key transcriptional programs is a critical mechanism that controls hematopoietic development, and, thus, aberrant expression patterns or mutations in epigenetic regulators occur frequently in hematologic malignancies. We demonstrate that the Polycomb protein L3MBTL1, which is monoallelically deleted in 20q- myeloid malignancies, represses the ability of stem cells to drive hematopoietic-specific transcriptional programs by regulating the expression of SMAD5 and impairing its recruitment to target regulatory regions. Indeed, knockdown of L3MBTL1 promotes the development of hematopoiesis and impairs neural cell fate in human pluripotent stem cells. We also found a role for L3MBTL1 in regulating SMAD5 target gene expression in mature hematopoietic cell pop-ulations, thereby affecting erythroid differentiation. Taken together, we have identified epigenetic priming of hematopoietic-specific transcriptional networks, which may assist in the development of therapeutic approaches for patients with anemia.


Sparks E.E.,Center for Stem Cell Biology | Huppert K.A.,Center for Stem Cell Biology | Brown M.A.,Center for Stem Cell Biology | Washington M.K.,Vanderbilt University | Huppert S.S.,Center for Stem Cell Biology
Hepatology | Year: 2010

Alagille syndrome, a chronic hepatobiliary disease, is characterized by paucity of intrahepatic bile ducts (IHBDs). To determine the impact of Notch signaling specifically on IHBD arborization, we studied the influence of both chronic gain and loss of Notch function on the intact three-dimensional IHBD structure using a series of mutant mouse models and a resin casting method. Impaired Notch signaling in bipotential hepatoblast progenitor cells (BHPCs) dose-dependently decreased the density of peripheral IHBDs, whereas activation of Notch1 results in an increased density of peripheral IHBDs. Although Notch2 has a dominant role in IHBD formation, there is also a redundant role for other Notch receptors in determining the density of peripheral IHBDs. Because changes in IHBD density do not appear to be due to changes in cellular proliferation of bile duct progenitors, we suggest that Notch plays a permissive role in cooperation with other factors to influence lineage decisions of BHPCs and sustain peripheral IHBDs. Conclusion: There is a threshold requirement for Notch signaling at multiple steps, including IHBD tubulogenesis and maintenance, during hepatic development that determines the density of three-dimensional peripheral IHBD architecture. Copyright © 2010 by the American Association for the Study of Liver Diseases.


Willet S.G.,Center for Stem Cell Biology | Willet S.G.,Vanderbilt University | Hale M.A.,University of Texas Southwestern Medical Center | Grapin-Botton A.,Copenhagen University | And 4 more authors.
Development (Cambridge) | Year: 2014

The timing and gene regulatory logic of organ-fate commitment from within the posterior foregut of the mammalian endoderm is largely unexplored. Transient misexpression of a presumed pancreaticcommitment transcription factor, Ptf1a, in embryonic mouse endoderm (Ptf1aEDD) dramatically expanded the pancreatic gene regulatory network within the foregut. Ptf1aEDD temporarily suppressed Sox2 broadly over the anterior endoderm. Pancreas-proximal organ territories underwent full tissue conversion. Early-stage Ptf1aEDD rapidly expanded the endogenous endodermal Pdx1-positive domain and recruited other pancreas-fate-instructive genes, thereby spatially enlarging the potential for pancreatic multipotency. Early Ptf1aEDD converted essentially the entire glandular stomach, rostral duodenum and extrahepatic biliary systemto pancreas,with formation of manyendocrine cell clusters of the type found in normal islets of Langerhans. Sliding the Ptf1aEDD expression window through embryogenesis revealed differential temporal competencies for stomach-pancreas respecification. The response to later-stage Ptf1aEDD changed radically towards unipotent, acinar-restricted conversion. We provide strong evidence, beyond previous Ptf1a inactivation or misexpression experiments in frog embryos, for spatiotemporally context-dependent activity of Ptf1a as a potent gain-of-function trigger of pro-pancreatic commitment. © 2014, Published by The Company of Biologists Ltd.

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