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Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.
Kropp PA, Dunn JC, Carboneau BA, Stoffers DA, Gannon M
(2018) Am J Physiol Endocrinol Metab 314: E308-E321
MeSH Terms: Adaptation, Physiological, Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Diet, High-Fat, Gene Expression Regulation, Developmental, Glucose, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Transgenic, Multipotent Stem Cells, Organogenesis, Trans-Activators
Show Abstract · Added April 15, 2019
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
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MeSH Terms
Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis.
Mobley BC, Kwon M, Kraemer BR, Hickman FE, Qiao J, Chung DH, Carter BD
(2015) PLoS One 10: e0133897
MeSH Terms: Adrenal Glands, Animals, Apoptosis, Carcinogenesis, Cell Differentiation, Cell Lineage, Cell Proliferation, Ganglia, Sympathetic, Gene Expression Regulation, Male, Mice, Mice, Nude, Multipotent Stem Cells, N-Myc Proto-Oncogene Protein, Neural Crest, Neural Stem Cells, Neuroblastoma, Neurons, Proto-Oncogene Proteins
Show Abstract · Added February 20, 2016
Neuroblastoma is a pediatric malignancy of the sympathetic ganglia and adrenal glands, hypothesized to originate from progenitors of the developing sympathetic nervous system. Amplification of the MYCN oncogene is a genetic marker of risk in this disease. Understanding the impact of oncogene expression on sympathoadrenal progenitor development may improve our knowledge of neuroblastoma initiation and progression. We isolated sympathoadrenal progenitor cells from the postnatal murine adrenal gland by sphere culture and found them to be multipotent, generating differentiated colonies of neurons, Schwann cells, and myofibroblasts. MYCN overexpression in spheres promoted commitment to the neural lineage, evidenced by an increased frequency of neuron-containing colonies. MYCN promoted proliferation of both sympathoadrenal progenitor spheres and differentiated neurons derived from these spheres, but there was also an increase in apoptosis. The proliferation, apoptosis, and neural lineage commitment induced by MYCN are tumor-like characteristics and thereby support the hypothesis that multipotent adrenal medullary progenitor cells are cells of origin for neuroblastoma. We find, however, that MYCN overexpression is not sufficient for these cells to form tumors in nude mice, suggesting that additional transforming mutations are necessary for tumorigenesis.
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19 MeSH Terms
Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells.
Sancho R, Gruber R, Gu G, Behrens A
(2014) Cell Stem Cell 15: 139-53
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Tumor, Cell Lineage, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Gene Deletion, Gene Expression Profiling, Gene Expression Regulation, Developmental, Glucagon-Secreting Cells, Glucose, HEK293 Cells, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Mice, Multipotent Stem Cells, Nerve Tissue Proteins, Pancreatic Ducts, Proteasome Endopeptidase Complex, Regeneration, Somatostatin-Secreting Cells, Ubiquitin-Protein Ligases, Ubiquitination
Show Abstract · Added January 23, 2015
The adult pancreas is capable of limited regeneration after injury but has no defined stem cell population. The cell types and molecular signals that govern the production of new pancreatic tissue are not well understood. Here, we show that inactivation of the SCF-type E3 ubiquitin ligase substrate recognition component Fbw7 induces pancreatic ductal cells to reprogram into α, δ, and β cells. Loss of Fbw7 stabilized the transcription factor Ngn3, a key regulator of endocrine cell differentiation. The induced β cells resemble islet β cells in morphology and histology, express genes essential for β cell function, and release insulin after glucose challenge. Thus, loss of Fbw7 appears to reawaken an endocrine developmental differentiation program in adult pancreatic ductal cells. Our study highlights the plasticity of seemingly differentiated adult cells, identifies Fbw7 as a master regulator of cell fate decisions in the pancreas, and reveals adult pancreatic duct cells as a latent multipotent cell type.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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26 MeSH Terms
The Par3-like polarity protein Par3L is essential for mammary stem cell maintenance.
Huo Y, Macara IG
(2014) Nat Cell Biol 16: 529-37
MeSH Terms: Animals, Apoptosis, Cell Adhesion Molecules, Cell Differentiation, Cell Polarity, Cell Proliferation, Cell Survival, Cells, Cultured, Female, Intracellular Signaling Peptides and Proteins, Keratin-8, Mammary Glands, Animal, Mice, Mice, Inbred C3H, Multipotent Stem Cells, Protein Binding, Protein-Serine-Threonine Kinases, RNA Interference, Signal Transduction, Tight Junctions, Transfection
Show Abstract · Added May 30, 2014
The Par polarity proteins play key roles in asymmetric division of Drosophila melanogaster stem cells; however, whether the same mechanisms control stem cells in mammals is controversial. Although necessary for mammary gland morphogenesis, Par3 is not essential for mammary stem cell function. We discovered that, instead, a previously uncharacterized protein, Par3-like (Par3L), is vital for mammary gland stem cell maintenance. Par3L function has been mysterious because, unlike Par3, it does not interact with atypical protein kinase C or the Par6 polarity protein. We found that Par3L is expressed by multipotent stem cells in the terminal end buds of murine mammary glands. Ablation of Par3L resulted in rapid and profound stem cell loss. Unexpectedly, Par3L, but not Par3, binds to the tumour suppressor protein Lkb1 and inhibits its kinase activity. This interaction is key for the function of Par3L in mammary stem cell maintenance. Our data reveal insights into a link between cell polarity proteins and stem cell survival, and uncover a biological function for Par3L.
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21 MeSH Terms
Human mesenchymal stromal cells: identifying assays to predict potency for therapeutic selection.
Deskins DL, Bastakoty D, Saraswati S, Shinar A, Holt GE, Young PP
(2013) Stem Cells Transl Med 2: 151-8
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Biomarkers, Bone Marrow Cells, Cell Differentiation, Cell Proliferation, Disease Models, Animal, Female, Flow Cytometry, Humans, Male, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells, Mice, Middle Aged, Multipotent Stem Cells, Predictive Value of Tests, Reproducibility of Results, Skin
Show Abstract · Added March 7, 2014
Multipotent mesenchymal stromal cells (MSCs) have the potential to repair and regenerate damaged tissues, making them attractive candidates for cell-based therapies. To maximize efficacy of MSCs, prediction of their therapeutic abilities must be made so that only the best cells will be used. Our goal was to identify feasible and reproducible in vitro assays to predict MSC potency. We generated cell lines from 10 normal human bone marrow samples and used the International Society for Cellular Therapy's minimal criteria to define them as MSCs: plastic adherence, appropriate surface marker expression, and trilineage differentiation. Each MSC line was further characterized by its growth, proliferation, and viability as determined by cell count, bromodeoxyuridine incorporation, and cellular ATP levels, respectively. To determine whether these tests reliably predict the therapeutic aptitude of the MSCs, several lines were implanted in vivo to examine their capacity to engraft and form granulation tissue in a well-established murine wound model using polyvinyl alcohol sponges. Long-term engraftment of MSCs in the sponges was quantified through the presence of the human-specific Alu gene in sponge sections. Sections were also stained for proliferating cells, vascularity, and granulation tissue formation to determine successful engraftment and repair. We found that high performance in a combination of the in vitro tests accurately predicted which lines functioned well in vivo. These findings suggest that reliable and reproducible in vitro assays may be used to measure the functional potential of MSCs for therapeutic use.
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21 MeSH Terms
Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration.
Pan FC, Bankaitis ED, Boyer D, Xu X, Van de Casteele M, Magnuson MA, Heimberg H, Wright CV
(2013) Development 140: 751-64
MeSH Terms: Acinar Cells, Animals, Body Weights and Measures, Cell Differentiation, Gene Knock-In Techniques, Mice, Microscopy, Confocal, Multipotent Stem Cells, Organogenesis, Pancreas, Recovery of Function, Signal Transduction, Tamoxifen, Time Factors, Transcription Factors
Show Abstract · Added January 10, 2014
Pancreatic multipotent progenitor cells (MPCs) produce acinar, endocrine and duct cells during organogenesis, but their existence and location in the mature organ remain contentious. We used inducible lineage-tracing from the MPC-instructive gene Ptf1a to define systematically in mice the switch of Ptf1a(+) MPCs to unipotent proacinar competence during the secondary transition, their rapid decline during organogenesis, and absence from the mature organ. Between E11.5 and E15.5, we describe tip epithelium heterogeneity, suggesting that putative Ptf1a(+)Sox9(+)Hnf1β(+) MPCs are intermingled with Ptf1a(HI)Sox9(LO) proacinar progenitors. In the adult, pancreatic duct ligation (PDL) caused facultative reactivation of multipotency factors (Sox9 and Hnf1β) in Ptf1a(+) acini, which undergo rapid reprogramming to duct cells and longer-term reprogramming to endocrine cells, including insulin(+) β-cells that are mature by the criteria of producing Pdx1(HI), Nkx6.1(+) and MafA(+). These Ptf1a lineage-derived endocrine/β-cells are likely formed via Ck19(+)/Hnf1β(+)/Sox9(+) ductal and Ngn3(+) endocrine progenitor intermediates. Acinar to endocrine/β-cell transdifferentiation was enhanced by combining PDL with pharmacological elimination of pre-existing β-cells. Thus, we show that acinar cells, without exogenously introduced factors, can regain aspects of embryonic multipotentiality under injury, and convert into mature β-cells.
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15 MeSH Terms
Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population.
Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L
(2012) PLoS One 7: e52026
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Ghrelin, Homeodomain Proteins, Islets of Langerhans, Mice, Mice, Inbred C57BL, Multipotent Stem Cells, Nerve Tissue Proteins, Transcription Factors
Show Abstract · Added January 14, 2013
Pancreatic islet cells provide the major source of counteractive endocrine hormones required for maintaining glucose homeostasis; severe health problems result when these cell types are insufficiently active or reduced in number. Therefore, the process of islet endocrine cell lineage allocation is critical to ensure there is a correct balance of islet cell types. There are four endocrine cell types within the adult islet, including the glucagon-producing alpha cells, insulin-producing beta cells, somatostatin-producing delta cells and pancreatic polypeptide-producing PP cells. A fifth islet cell type, the ghrelin-producing epsilon cells, is primarily found during gestational development. Although hormone expression is generally assumed to mark the final entry to a determined cell state, we demonstrate in this study that ghrelin-expressing epsilon cells within the mouse pancreas do not represent a terminally differentiated endocrine population. Ghrelin cells give rise to significant numbers of alpha and PP cells and rare beta cells in the adult islet. Furthermore, pancreatic ghrelin-producing cells are maintained in pancreata lacking the essential endocrine lineage regulator Neurogenin3, and retain the ability to contribute to cells within the pancreatic ductal and exocrine lineages. These results demonstrate that the islet ghrelin-expressing epsilon cells represent a multi-potent progenitor cell population that delineates a major subgrouping of the islet endocrine cell populations. These studies also provide evidence that many of hormone-producing cells within the adult islet represent heterogeneous populations based on their ontogeny, which could have broader implications on the regulation of islet cell ratios and their ability to effectively respond to fluctuations in the metabolic environment during development.
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11 MeSH Terms
Lineage determinants in early endocrine development.
Rieck S, Bankaitis ED, Wright CV
(2012) Semin Cell Dev Biol 23: 673-84
MeSH Terms: Animals, Gene Regulatory Networks, Humans, Islets of Langerhans, Multipotent Stem Cells, Organogenesis, Pancreas
Show Abstract · Added March 7, 2014
Pancreatic endocrine cells are produced from a dynamic epithelium in a process that, as in any developing organ, is driven by interacting programs of spatiotemporally regulated intercellular signals and autonomous gene regulatory networks. These algorithms work to push progenitors and their transitional intermediates through a series of railroad-station-like switching decisions to regulate flux along specific differentiation tracks. Extensive research on pancreas organogenesis over the last 20 years, greatly spurred by the potential to restore functional β-cell mass in diabetic patients by transplantation therapy, is advancing our knowledge of how endocrine lineage bias is established and allocation is promoted. The field is working towards the goal of generating a detailed blueprint of how heterogeneous cell populations interact and respond to each other, and other influences such as the extracellular matrix, to move into progressively refined and mature cell states. Here, we highlight how signaling codes and transcriptional networks might determine endocrine lineage within a complex and dynamic architecture, based largely on studies in the mouse. The process begins with the designation of multipotent progenitor cells (MPC) to pancreatic buds that subsequently move through a newly proposed period involving epithelial plexus formation-remodeling, and ends with formation of clustered endocrine islets connected to the vascular and peripheral nervous systems. Developing this knowledge base, and increasing the emphasis on direct comparisons between mouse and human, will yield a more complete and focused picture of pancreas development, and thereby inform β-cell-directed differentiation from human embryonic stem or induced pluripotent stem cells (hESC, iPSC). Additionally, a deeper understanding may provide surprising therapeutic angles by defining conditions that allow the controllable reprogramming of endodermal or pancreatic cell populations.
Copyright © 2012 Elsevier Ltd. All rights reserved.
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7 MeSH Terms
Endothelial differentiation by multipotent fetal mouse lung mesenchymal cells.
Yamamoto Y, Baldwin HS, Prince LS
(2012) Stem Cells Dev 21: 1455-65
MeSH Terms: Animals, Antigens, Differentiation, Cell Differentiation, Cells, Cultured, Embryo, Mammalian, Endothelial Cells, Fibroblast Growth Factor 2, Lung, Mesenchymal Stem Cells, Mice, Mice, Transgenic, Multipotent Stem Cells, Neovascularization, Physiologic, Vascular Endothelial Growth Factor A
Show Abstract · Added December 5, 2013
During fetal lung development, cells within the mesenchyme differentiate into vascular endothelia. This process of vasculogenesis gives rise to the cells that will eventually form the alveolar capillary bed. The cellular mechanisms regulating lung vasculogenesis are poorly understood, partly due to the lack of experimental systems that model this process. Here, we have developed and characterized a novel fetal mouse lung cell model of mesenchymal to endothelial differentiation. Using mesenchymal cells from the lungs of embryonal day 15 Immortomice, we show that endothelial growth media containing fibroblast growth factor-2 and vascular endothelial growth factor can stimulate formation of vascular endothelial cells in culture. These newly formed endothelial cells retain plasticity, as removing endothelial growth media causes loss of vascular markers and renewed formation of α-smooth muscle actin positive stress fibers. Cells with the highest Flk-1 expression differentiated into endothelia more efficiently. Individual mesenchymal cell clones had varied ability to acquire an endothelial phenotype. These fetal lung mesenchymal cells were multipotent, capable of differentiating into not only vascular endothelia, but also osteogenic and chondrongenic cell lineages. Our data establish a cell culture model for mesenchymal to endothelial differentiation that could prove useful for future mechanistic studies in the process of vasculogenesis both during normal development and in the pathogenesis of pulmonary vascular disease.
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14 MeSH Terms
Neural crest stem cell multipotency requires Foxd3 to maintain neural potential and repress mesenchymal fates.
Mundell NA, Labosky PA
(2011) Development 138: 641-52
MeSH Terms: Animals, Cell Differentiation, Cell Lineage, Embryo, Mammalian, Forkhead Transcription Factors, Gene Expression Regulation, Developmental, Mice, Mice, Knockout, Multipotent Stem Cells, Mutation, Neural Crest, Neural Stem Cells, Repressor Proteins
Show Abstract · Added March 31, 2011
Neural crest (NC) progenitors generate a wide array of cell types, yet molecules controlling NC multipotency and self-renewal and factors mediating cell-intrinsic distinctions between multipotent versus fate-restricted progenitors are poorly understood. Our earlier work demonstrated that Foxd3 is required for maintenance of NC progenitors in the embryo. Here, we show that Foxd3 mediates a fate restriction choice for multipotent NC progenitors with loss of Foxd3 biasing NC toward a mesenchymal fate. Neural derivatives of NC were lost in Foxd3 mutant mouse embryos, whereas abnormally fated NC-derived vascular smooth muscle cells were ectopically located in the aorta. Cranial NC defects were associated with precocious differentiation towards osteoblast and chondrocyte cell fates, and individual mutant NC from different anteroposterior regions underwent fate changes, losing neural and increasing myofibroblast potential. Our results demonstrate that neural potential can be separated from NC multipotency by the action of a single gene, and establish novel parallels between NC and other progenitor populations that depend on this functionally conserved stem cell protein to regulate self-renewal and multipotency.
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13 MeSH Terms