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Development of the endocrine pancreas proceeds through a number of progenitor stages (blue), on the way specifying other cell types in the gastrointestinal system (purple) and the exocrine pancreas (green). Doug Melton's laboratory is interested in the genes and stem cells that give rise to the pancreas and insulin-producing beta cells, with possible therapeutic implications for diabetes.
Type 1 or juvenile diabetes is a genetically complex disease caused by an autoimmune destruction of insulin-producing beta (?) cells. We analyze the genes and cells that form the pancreas and use that information to direct differentiation of multipotent stem cells toward the ?-cell fate. We are extending our work now, with collaborators, to explore ways to protect stem cell-derived beta cells from immune destruction folllowing transplantation.
We use a wide variety of techniques, including functional genomics, chemical screening, tissue explants and grafting for analyzing inductive signals, and developmental genetics for direct assays of gene function. Should we be successful in directing the differentiation of human cells into functional ? cells, or find signals that cause ? cell replication and regeneration in vivo, we will extend our findings to clinical applications for the treatment of diabetes. Some of these projects were also supported by grants from the National Institutes of Health, the Beta Cell Biology Consortium, the Juvenile Diabetes Research Foundation, and the Harvard Stem Cell Institute. Free resources for science teachers and students, including animations, short films, and apps. HHMI’s science magazine explores biomedical research through in-depth features, news, and perspectives. HHMI’s innovative research center where scientists pursue challenging problems in a collaborative setting. In the basic stage of this research, the researchers demonstrated that neurons have the intrinsic capacity to produce insulin as pancreatic cells have and elucidated the mechanism for activation of this capacity. Transplantation of pancreatic islets (islets of Langerhans) from the pancreas of a different donor is an effective treatment method for type-1 diabetes. AIST has been analyzing intracerebral neural stem cells and research has been carried out for use in development of medical treatments and drug discovery for Alzheimer’s disease and depression. This research was supported by a Grant-in-Aid for Scientific Research (B; Grant-in-Aid for Young Scientists) of the Japan Society for the Promotion of Science and by Suzuken Memorial Foundation. Adult neural stem cells were collected from both the hippocampi and the olfactory bulbs of rats and cultured.
Neural stem cell lines were established from both the hippocampi and the olfactory bulbs of diabetic rats and the results of transplantation were investigated. An investigation was carried out using antibody stains to determine which cells produce insulin in the diabetic rat pancreas fifteen weeks after the transplantation of adult neural stem cells. These results indicate that diabetes was alleviated by intrapancreatic insulin production when neural stem cells derived from the hippocampi or the olfactory bulbs of diabetic rats were transplanted.
Since the developed method is based on transplantation of autologous cells (adult stem cells from the olfactory bulb), there are no donor problems and no concerns about the adverse effects of immunosuppressive agents and it would lead to more natural regenerative therapy. Based on data obtained by analysis of the mechanism of insulin production by adult neural stem cells, research and development will be carried out on the effects on neurons themselves and on the search of activating agents for more effective insulin production. The Diabetes Media Foundation is a 501(c)(3) tax-exempt nonprofit media organization devoted to informing, educating, and generating community around living a healthy life with diabetes. The term "cancer" describes a group of diseases that are characterized by uncontrolled cellular growth, cellular invasion into adjacent tissues, and the potential to metastasize if not treated at a sufficiently early stage. The CSC hypothesis suggests that the malignancies associated with cancer originate from a small population of stem-like, tumor-initiating cells.
The identification of leukemia-inducing cells has fostered an intense effort to isolate and characterize CSCs in solid tumors. Given the similarities between tumor-initiating cells and stem cells, researchers have sought to determine whether CSCs arise from stem cells, progenitor cells, or differentiated cells present in adult tissue.
Several characteristics of the leukemia-initiating cells support the stem-cell origin hypothesis.
The differentiation pathway from a stem cell to a differentiated cell usually involves one or more intermediate cell types. Some researchers have suggested that cancer cells could arise from mature, differentiated cells that somehow de-differentiate to become more stem celllike. Some researchers have proposed that these unique cells may be CSCs.9,30,32,33,38 In this hypothesis, metastatic inefficiency may reflect the relative rarity of CSCs combined with the varying compatibilities of these cells with destination microenvironments. As noted previously, most contemporary cancer treatments have limited selectivity — systemic therapies and surgeries remove or damage normal tissue in addition to tumor tissue.
The CSC hypothesis accounts for observed patterns of cancer recurrence and metastasis following an apparently successful therapeutic intervention.
These discoveries have led researchers to propose several avenues for treating cancer by targeting molecules involved in CSC renewal and proliferation pathways.
Differentiation and regeneration in the pancreasDifferentiation and regeneration in the pancreasDiabetes is rapidly becoming a global epidemic, with a staggering health, societal, and economic impact.
Figure VIII-1: Embryonic pancreas developmentIn type 1 diabetes, autoimmune destruction of the ? cell itself severely reduces ?-cell mass, resulting in marked hypoinsulinemia and potentially life threatening ketoacidosis. Regeneration of beta cells (teal) in mice from acinar tissue by transduction of three genes13 and from alpha cells by conditional expression of one gene14 have demonstrated the feasibility of this approach to increase the number of beta cells in vivo. Wagner is in the Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. Thus, the challenge finding new treatments or a cure can be divided into two problems: blocking or reversing the autoimmune attack and providing new ? cells.
Genetic marking in mice has allowed us to map the lineage of progenitor cells that give rise to the exocrine, endocrine, and ductal components of the pancreas. Adult neural stem cell lines, which develop into neural cells, can be established and cultured not only by intracerebral collection, which requires difficult surgery, but also by collection from the olfactory bulb, which is relatively easy.
If people with pre-diabetic conditions are included, the total number is estimated to be as high as 10 to 20 million.
However, because of the characteristics of the pancreas that contains large amounts of digestive enzymes, in order to obtain a pancreas that can be transplanted, the necessary preparation includes searching for a potential donor while still alive and ascertaining compatibility. In the course of this research, it was realized that the regulatory mechanism of adult neural stem cells are closely similar to that of the pancreatic cellular lineage. In recent years, it has been shown that neural stem cells are present in the adult olfactory bulb and give rise to neurogenesis. Comparative analyses of gene expression were carried out using a micro-array method to investigate the expression of genes such as those essential for insulin production and those important for differentiation.
After culturing the neural stem cells for two weeks in cell culture solutions containing agents that promote insulin production, they were transplanted into the pancreases of diabetic rats.
In order to distinguish the transplanted adult neural stem cells from the original cells of the diabetic rats, the transplanted cells were prepared to express a green fluorescent protein as a marker. The insulin-producing cells are continuously replenished by adult neural stem cells and therapeutic efficacy is thus maintained.
Surgery, radiation therapy, and systemic treatments such as chemotherapy or hormonal therapy represent traditional approaches designed to remove or kill rapidly-dividing cancer cells. Tumors originate from the transformation of normal cells through the accumulation of genetic modifications, but it has not been established unequivocally that stem cells are the origin of all CSCs.
Although cancer researchers first isolated CSCs in 1994,14 the concept dates to the mid-19th century.
Stem cell-like populations have since been characterized using cell-surface protein markers in tumors of the breast,17 colon,18 brain,19 pancreas,20,21 and prostate.22,23 However, identifying markers that unequivocally characterize a population of CSCs remains challenging, even when there is evidence that putative CSCs exist in a given solid tumor type. Stem cells are distinguished from other cells by two characteristics: (1) they can divide to produce copies of themselves, or self-renew, under appropriate conditions and (2) they are pluripotent, or able to differentiate into most, if not all, mature cell types.
Recently, the CSCs associated with AML have been shown to comprise distinct, hierarchically-arranged classes (similar to those observed with hematopoietic stem cells) that dictate distinct fates.31 To investigate whether these CSCs derive from hematopoietic stem cells, researchers have used a technique known as serial dilution to determine the CSCs' ability to self-renew.
These intermediate cells, which are more abundant in adult tissue than are stem cells, are called progenitor or precursor cells.
In this scenario, the requisite oncogenic (cancer causing) genetic mutations would need to drive the de-differentiation process as well as the subsequent self-renewal of the proliferating cells. These methods must therefore be employed judiciously to limit adverse effects associated with treatment. In clinical practice, however, some cancers prove quite aggressive, resisting chemotherapy or radiation even when administered at relatively early stages of tumor progression.
In the face of radiation, the CSCs appear to survive preferentially, repair their damaged DNA more efficiently, and begin the process of self-renewal. Potential strategies include interfering with molecular pathways that increase drug resistance, targeting proteins that may sensitize CSCs to radiation, or restraining the CSCs' self-renewal capacity by modifying their cell differentiation capabilities.9 In each case, successful development of a therapy would require additional basic and clinical research.

Governed by an intricate, complex interplay of molecular signals, cancers often resist systemic treatments. Cancer stem cell science is an emerging field that will ultimately impact researchers' understanding of cancer processes and may identify new therapeutic strategies.
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
Targeted therapy for the treatment of advanced non-small cell lung cancer: a review of the epidermal growth factor receptor antagonists. Cancer Stem Cells—Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells. Human myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Stem-cell abundant proteins Nanog, Nucleostemin and Musashi1 are highly expressed in malignant cervical epithelial cells. Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis.
Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity.
Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.
Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells.
Recent estimates by the American Diabetes Association suggest that the lifetime risk of developing diabetes for Americans born in the year 2000 is one in three. In contrast, during the progression to type 2 diabetes, impaired ?-cell compensation in the setting of insulin resistance (impaired insulin action) eventually leads to ?-cell failure and a modest but significant reduction in ?-cell mass. Recently, procedures have been developed to derive and maintain hESCs on human feeder cells as well as feeder-free matrices in various growth factor-supplemented basal media. We have focused on the latter, pursuing three complementary approaches aimed at making new ? cells for diabetics. In parallel, using biological and chemical screens, we investigate the regulatory genes that specify pancreatic cell fates. It has been confirmed that, when adult neural stem cells are collected from diabetic rats, established as cultures, and transplanted into the pancreases of diabetic rats once a state of ready insulin production has been achieved, a decreased blood sugar level can be maintained. Numerous diabetes patients suffer increased severity after the onset, involving complications such as retinopathy and nephropathy, and an important issue is therefore the establishment of radical diabetes treatments. As a result, the problem of shortage of donors for pancreatic islet transplantation is extremely serious. The mechanism was then analyzed in more detail, because these findings relate to techniques in which neural stem cells are used as substitutes for cells that function in the pancreas and offer the potential for use in regenerative therapy for diabetes and pancreatic disease. In addition, during basic research relating to adult neural stem cells, it was found that the genes required for insulin production are expressed in adults in both the pancreas and the cerebral nervous system. The findings showed that the genes for insulin production are expressed during the process of differentiation to neurons in both neural stem cells derived from the hippocampus and those derived from the olfactory bulb. Blood sugar levels of the rats indicating their diabetic disease states were measured regularly and it was found that, whether the transplanted neural stem cell line was derived from the hippocampus or the olfactory bulb, the blood sugar levels gradually decreased, indicating that the diabetes was alleviated.
It was confirmed that almost no insulin was produced in the islets of Langerhans of the diabetic rats, whereas the transplanted neural stem cells (the green cells in Fig. Another advantage is that the treatment has a low carcinogenesis risk and is very safe because the treatment involves no gene transfer. For example, in 2000, the relative survival rate five years following diagnosis of melanoma (skin cancer) was greater than 90%; that of cancers of the brain and nervous system was 35%.
Tumors and other structures that result from aberrant cell growth, contain heterogeneous cell populations with diverse biological characteristics and potentials. The CSC hypothesis therefore does not imply that cancer is always caused by stem cells or that the potential application of stem cells to treat conditions such as heart disease or diabetes, as discussed in other chapters of this report, will result in tumor formation. The issue is currently under debate,9,12 and this section will review several theories about the cellular precursors of cancer cells (see Fig. The molecular pathways that maintain "stem-ness" in stem cells are also active in numerous cancers. If CSCs arise from normal stem cells present in the adult tissue, de-differentiation would not be necessary for tumor formation. Serial dilution involves transplanting cells (usually hematopoietic stem cells, but in this case, CSCs) into a mouse during a bone-marrow transplant.
They are partly differentiated cells present in fetal and adult tissues that usually divide to produce mature cells. This model leaves open the possibility that a relatively large population of cells in the tissue could have tumorigenic potential; a small subset of these would actually initiate the tumor. Moreover, these approaches are often only temporarily effective; cancers that appear to be successfully eliminated immediately following treatment may recur at a later time and often do so at a new site. These tumors therefore have an increased likelihood of metastasizing, confounding further treatment strategies while compromising the cancer patient's quality of life. Researchers must characterize the CSCs associated with a given tumor type, identify relevant molecules to target, develop effective agents, and test the agents in pre-clinical models, such as animals or cell lines. Yet the uncontrolled cellular growth that characterizes cancers may paradoxically hold the key to understanding the spread of disease.
However, much remains to be learned about these unique cells, which as of yet have not been identified in all tumor types.
Diabetes results when insulin production by the pancreatic islet ? cell is unable to meet the metabolic demand of peripheral tissues such as liver, fat, and muscle.
More recently, autoimmunity has been detected in a subset of patients with type 2 diabetes, which has led to a revision of the classification to include LADA, latent autoimmune diabetes of adulthood, underscoring the continuum between type 1 and type 2 diabetes, and raising questions as to the role of immunity and inflammation in ?-cell dysfunction and death in type 2 diabetes.
In addition, hESCs can be transferred from feeders to feeder-free conditions and vice versa without affecting their pluripotency, although such transfers do affect their protein expression profile. These studies have identified a set of transcription factors and intercellular signaling molecules (growth factors) that are responsible for the stepwise differentiation of normal pancreatic development. This technique has the potential for use in safer and more natural regenerative medicine using autologous cells without gene transfer.
There are also other problems with this treatment method, including its high medical cost due to the need for concomitant post-transplantation administration of immunosuppressive agents and the decrease in metabolic activity due to the immunosuppressive agents. Cutting-edge research on adult neural stem cells has also been carried out at the Salk Institute for Biological Studies in the USA. In terms of application to regenerative medicine involving collection of autologous cells and use of them as the cell source for transplantation, endoscopic collection of neural stem cells from the olfactory bulb is preferable to collection of intracerebral neural stem cells by means of difficult surgery. In contrast, the diabetic rat group that did not undergo neural stem cell transplantation suffered marked deterioration in the disease state and died after eight weeks (* in Fig. This method could be used as a preliminary treatment during the stage before the onset of serious complications (retinopathy and nephropathy) and could be applied to a wide range of indications. AFFAIRSPOLITICSBUSINESSLIFESTYLEPEOPLESPORTSDIPLOMACYCRIMEINDIAPOLITICSBUSINESSSOUTH ASIAPAKISTANBANGLADESHSRI LANKANEPALBHUTANENTERTAINMENTCINEMAMUSICLIFESTYLEFASHIONRELIGIONCUISINEBUSINESSOPINIONBLOGSPassage To India Diabetes Researcher Named Harvard Medical School ProfessorBy Suman Guha MozumderRohit N. Once a cancer has metastasized (or spread to secondary sites via the blood or lymph system), however, the survival rate usually declines dramatically. As such, a researcher sequencing all of the genes from tumor specimens of two individuals diagnosed with the same type of lung cancer will identify some consistencies along with many differences.
For example, cancer surgeons may be unable to remove all of the tumor tissue due to its location or extent of spreading. For instance, the proteins Nanog, nucleostemin, and musashi1, which are highly expressed in embryonic stem cells and are critical to maintaining those cells' pluripotency, are also highly expressed in malignant cervical epithelial cells.27 While this finding does not indicate the existence of cervical cancer CSCs, it suggests that these proteins may play roles in cervical carcinogenesis and progression.
This similarity has led scientists to propose that cancers may arise when some event produces a mutation in a stem cell, robbing it of the ability to regulate cell division. In this scenario, cancer cells could simply utilize the existing stem-cell regulatory pathways to promote their self-renewal. Prior to the transplant, this "primary recipient" mouse's natural supply of hematopoietic stem cells is ablated.

Agents that target molecules implicated in cancer pathways have illustrated the power of a selective approach, and many researchers and drug developers are shifting toward this paradigm.
However, by targeting fundamental CSC cellular signaling processes, it is possible that a given treatment could be effective against multiple tumor types. It has long been postulated that tumors form and proliferate from the actions of a small population of unique cells. At present, evidence continues to mount to support a CSC Hypothesis—that cancers are perpetuated by a small population of tumor-initiating cells that exhibit numerous stem cell-like properties. Conversely, forms of ketosis prone diabetes due to severe ? cell dysfunction but without evidence of autoimmunity are now recognized.
Irrespectively, advancements like these allow the generation of clinical grade cell lines by omitting non human components. This genetic and cellular knowledge of pancreatic developmental biology guides our approach to the directed differentiation of stem cells.
Stem cell transplantation can be used as an alternative to pancreatic islet transplantation, but an important issue is how efficiently and safely stem cells for use in transplantation can be prepared.
Kulkarni, senior Investigator in the Section on Islet Cell and Regenerative Biology at Joslin Diabetes Center, world-renowned for its deep expertise in diabetes treatment and research, has been named Professor of Medicine by Harvard Medical School.Dr. In fact, cancerous tissues are sufficiently heterogeneous that the researcher will likely identify differences in the genetic profiles between several tissue samples from the same specimen.
Radiation and chemotherapy, on the other hand, are non-specific strategies—while targeting rapidly-dividing cells, these treatments often destroy healthy tissue as well. Subsequent analysis of populations of leukemia-initiating cells from various AML subtypes indicated that the cells were relatively immature in terms of differentiation.16 In other words, the cells were "stem-like"—more closely related to primitive blood-forming (hematopoietic) stem cells than to more mature, committed blood cells.
This figure illustrates 3 hypotheses of how a cancer stem cell may arise: (1) A stem cell undergoes a mutation, (2) A progenitor cell undergoes two or more mutations, or (3) A fully differentiated cell undergoes several mutations that drive it back to a stem-like state.
The ability to self-renew gives stem cells long lifespans relative to those of mature, differentiated cells.30 It has therefore been hypothesized that the limited lifespan of a mature cell makes it less likely to live long enough to undergo the multiple mutations necessary for tumor formation and metastasis. If the transplant is successful and if the cells undergo substantial self-renewal, the primary recipient can then become a successful donor for a subsequent, or serial, transplant. However, if a tissue contains a sufficient population of differentiated cells, the laws of probability indicate that a small portion of them could, in principle, undergo the sequence of events necessary for de-differentiation.
If the CSC hypothesis proves to be correct, then a strategy designed to target CSCs selectively could potentially stop the "seeds" of the tumor before they have a chance to germinate and spread.
The observation that metastatic cancer cells exhibit experimental and clinical behaviors highly reminiscent of the classical properties of stem cells has led researchers to search for and to characterize "cancer stem cells" believed to be implicated in the cancer process. Whether or not the Hypothesis ultimately proves true in all cases, understanding the similarities between cancer cells and stem cells will illuminate many molecular pathways that are triggered in carcinogenesis.
Using both embryonic and induced pluripotent stem cells (ES and iPS, respectively, from mice and humans), we aim to create functional ? cells, using a stepwise differentiation protocol wherein specific signals are used to tell the cells which fate to adopt. Therefore, in order to achieve long-term stabilization of post-transplantation patients, there is a need for safer stem cells that have properties compatible with the pancreas into which they are transplanted and that can be used without operations such as gene transfer that might cause future carcinogenesis, etc. Gage of that Institute, the properties and capacities of these cells have been analyzed in detail using adult neural stem cells from the adult hippocampus and also from the olfactory bulb, from which cells can be collected more readily. In addition, when the transplanted neural stem cells were removed from the alleviated diabetic rats (the broken-line arrow in Fig.2), the blood sugar level again increased. While some groupings of genes allow scientists to classify organ-or tissue-specific cancers into subcategories that may ultimately inform treatment and provide predictive information, the remarkable complexity of cancer biology continues to confound treatment efforts. Recently, several agents that target specific proteins implicated in cancer-associated molecular pathways have been developed for clinical use. In all 3 scenarios, the resultant cancer stem cell has lost the ability to regulate its own cell division. Following cell division within primary recipients, a subset of the AML-associated CSCs divided only rarely and underwent self-renewal instead of committing to a lineage. Numerous groups have reported the derivation of endocrine hormone-expressing cells from spontaneously differentiating cultures. These include trastuzumab, a monoclonal antibody that targets the protein HER2 in breast cancer,5 gefitinib and erlotnib, which target epidermal growth factor receptor (EGFR) in lung cancer,6 imatinib, which targets the BCR-ABL tyrosine kinase in chronic myelogenous leukemia,7 the monoclonal antibodies bevacizumab, which targets vascular endothelial growth factor in colorectal and lung cancer,8 and cetuximab and panitumumab, which target EGFR in colorectal cancer.8 These agents have shown that a targeted approach can be successful, although they are effective only in patients who feature select subclasses of these respective cancers. However, the characterization of CSCs will likely play a role in the development of novel targeted therapies designed to eradicate the most dangerous tumor cells, that may be resistant to current chemotherapy regimens, thereby providing researchers and clinicians with additional targets to alleviate the burden of cancer. Retinoic acid-mediated signaling plays a critical role in this patterning of the foregut and prospective pancreatic domain, and acts upstream of key transcription factors such as Pdx1, which is crucial for pancreas development.
Hence, the first protocols designed to promote differentiation into insulin-secreting cells specifically were developed for mESCs. He is internationally recognized for his work with beta cell growth and regeneration, a topic that is critical to the treatment and cure of diabetes,” said George King, Chief Scientific Officer at Joslin Diabetes Center and Professor of Medicine at Harvard Medical School. Notably, while these transcription factors are critical for the patterning and eventual development and function of the pancreas, none are absolutely restricted to cells of the pancreatic lineage, or even endoderm.
These protocols relied on either transfection with an expression construct harboring an antibiotic resistance gene under control of the insulin promoter, or embryoid body formation.
Kulkarni as a faculty member at Joslin and look forward to collaborating with him in the years to come.”Kulkarni joined Joslin and the Harvard Medical School faculty in 1999. Distinct signaling events guide dorsal and ventral bud development, although suppression of hedgehog signaling plays an important role in both.
Then, addition of Fgf10 and the hedgehog signaling inhibitor cyclopamine and the subsequent addition of RA led to the generation of primitive gut tube-like cells marked by HNF1 and HNF4, followed by posterior foregut-like cells that expressed Pdx1, HNF6, and Hb9. He has held several leadership roles at Joslin, including the Director of the Diabetes Endocrinology Research Center Specialized Assay Core from 2002 to 2012. Initially, Shh expression extends throughout the anterior–posterior axis of the developing gut tube endoderm, but is repressed specifically in the dorsal and ventral pancreatic buds by notochord signaling via FGF2 (basic FGF) and Activin.
In contrast, FGF2 signaling from the cardiac mesoderm induces liver-specific differentiation of the ventral bud, which has a pancreatic fate when FGF2 is absent. GLP-1 promotes fetal ? cell maturation in culture, and HGF is a ?-cell mitogen, whereas IGF-1 plays postnatal roles in ? cell differentiation and survival.
Thus, by attempting to recapitulate the signaling cascades governing embryonic development and ? cell differentiation, cells expressing a transcription factor signature resembling that of ? cells were generated from ES cells.More specific multistage procedures developed for the differentiation of mESCs into neural tissues also generated cells containing islet hormones.
Interestingly, Mnx1 is required for the expansion of the dorsal bud, and Hhex is required for the ventral bud, while FGF10 from the overlying dorsal mesenchyme regulates the growth of the pancreatic epithelium in both the dorsal and the ventral pancreatic buds. However, the absence of C-peptide as well as insulin mRNA revealed that intracellular insulin did not originate from de novo synthesis in these cells, but from uptake from the culture media. John’s Medical College and the Royal Postgraduate Medical School, University of London, England respectively.
Expansion of the dorsal and ventral pancreatic buds continues, during which the gut rotates and brings the two pancreatic rudiments in closer proximity around e12.5. In addition, most of the islet markers used, such as the transcription factors described above, cannot uniquely identify cells of the pancreatic lineage, because they also mark cells of other lineages, especially neural ectoderm. While the connection of the dorsal part to the duodenum diminishes, that of the ventral part will form the main duct. Recently, the protocol developed originally for the differentiation of mESCs was modified and applied to hESCs, but the characterization of the cells generated in this study is fairly limited. Ronald Kahn, chief academic officer and senior investigator at Joslin Diabetes Center and the Mary K. Differentiation of the endocrine cells initiates slightly earlier in the dorsal bud than in the ventral bud, with glucagon-positive cells appearing first at ?e9.5. Differentiation of the endocrine cells requires the transient expression of the transcription factor Ngn3, which commits individual cells in the pancreatic epithelium to the endocrine lineage. At ?e13, a secondary transition that peaks around e14.5 initiates, during which a second wave of Ngn3 expression occurs. Ngn3 activates the expression of a number of endocrine transcription factors including Neurod1, Pax4, and Nkx2.2, the latter two of which govern the further differentiation into ?-cells.
Eventually, the combinatorial expression of multiple factors defines the identity of the specific endocrine cells present in islets.

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