The zinc finger transcription factor PW1/PEG3 restrains murine beta cell cycling (original) (raw)
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Expression Pattern of Stem Cell Markers in Developing Mouse Pancreas
Pakistan Veterinary Journal
Identification of stem cells in-vivo opens up the possibility of their expansion invitro, exploiting their multipotency in treating diabetes type 1 and type 2. Little is known about the relationship between a common pancreatic transcription factor (Pdx-1) and stem cell markers (CK19, CD29, CD56) in mice during pancreatic organogenesis. In this study the focused was on the prenatal immunohistochemical expression of stem cell markers (Pdx-1, CK19, CD29, and CD56) with special reference to their site and degree of expression during the prenatal pancreatic organogenesis. Material and Methods: Whole embryos and pancreatic tail of different prenatal groups (days 13, 15, & 18) were stained by H&E and immunohistochemically stained for Pdx-1 and stem cell markers, CK19, CD29, and CD56. Data was statistically analyzed for the evaluation of changes in the pattern and the degree of expression of stem cell markers in the pancreas. Results: Pdx-1 a transcription factor with role in pancreatic organogenesis was expressed in the duct, acini and islets in all ages. CK19 was expressed in the duct at day 13 and 15 prenatally, but in islet at day 18. Acinus and islets were positive for CK19 at all ages. CD29 on the other hand had positive expression in the duct while acini and islets had it at day 18 only. The acinar and islet cells were positive for CD56 at day 18 only. In conclusion, PDX-1 a transcription factor is vital in early pancreatic organogenesis whereas CK19, CD26 and CD56 are purportedly involved in generation of β-cells.
Molecular and Cellular Endocrinology, 2008
In recent years major progress has been made in understanding the role of transcription factors in the development of the endocrine pancreas in the mouse. Here we describe how a number of these transcription factors play a role in maintaining the differentiated phenotype of the β cell, and in the mechanisms that allow the β cell to adapt to changing metabolic demands that occur throughout life. Amongst these factors, Pdx1 plays a critical role in defining the region of the primitive gut that will form the pancreas, Ngn3 expression drives cells towards an endocrine lineage, and a number of additional proteins including Pdx1, in a second wave of expression, Pax4, NeuroD1/β2, and MafA act as β cell differentiation factors. In the mature β cell Pdx1, MafA, β2, and Nkx2.2 play important roles in regulating expression of insulin and to some extent other genes responsible for maintaining β cell function. We emphasise here that data from gene expression studies in rodents seldom map on to the known structure of the corresponding human promoters. In the adult the β cell is particularly susceptible to autoimmune mediated attack and to the toxic metabolic milieu associated with over-eating, and utilises a number of these transcription factors in its defence. Pdx1 has anti-apoptotic and proliferative activities that help facilitate the maintenance of β cell mass, while Ngn3 may be involved in the recruitment of progenitor cells, and Pax4 (and possibly HNF1α and Hnf4α) in the proliferation of β cells in the adult pancreas. Other transcription factors with a more widespread pattern of expression that play a role in β survival or proliferation include Foxo1, CREB family members, NFAT, FoxM1, Snail and Asc-2.
β Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas
Cell, 2008
Novel strategies in diabetes therapy would obviously benefit from the use of beta (b) cell stem/progenitor cells. However, whether or not adult b cell progenitors exist is one of the most controversial issues in today's diabetes research. Guided by the expression of Neurogenin 3 (Ngn3), the earliest islet cell-specific transcription factor in embryonic development, we show that b cell progenitors can be activated in injured adult mouse pancreas and are located in the ductal lining. Differentiation of the adult progenitors is Ngn3 dependent and gives rise to all islet cell types, including glucose responsive b cells that subsequently proliferate, both in situ and when cultured in embryonic pancreas explants. Multipotent progenitor cells thus exist in the pancreas of adult mice and can be activated cell autonomously to increase the functional b cell mass by differentiation and proliferation rather than by self-duplication of pre-existing b cells only.
Tshz1 Regulates Pancreatic β-Cell Maturation
Diabetes, 2015
The homeodomain transcription factor Pdx1 controls pancreas organogenesis, specification of endocrine pancreas progenitors, and the postnatal growth and function of pancreatic β-cells. Pdx1 expression in human-derived stem cells is used as a marker for induced pancreatic precursor cells. Unfortunately, the differentiation efficiency of human pancreatic progenitors into functional β-cells is poor. In order to gain insight into the genes that Pdx1 regulates during differentiation, we performed Pdx1 chromatin immunoprecipitation followed by high-throughput sequencing of embryonic day (e) 13.5 and 15.5 mouse pancreata. From this, we identified the transcription factor Teashirt zinc finger 1 (Tshz1) as a direct Pdx1 target. Tshz1 is expressed in developing and adult insulin- and glucagon-positive cells. Endocrine cells are properly specified in Tshz1-null embryos, but critical regulators of β-cell (Pdx1 and Nkx6.1) and α-cell (MafB and Arx) formation and function are downregulated. Adult...
No evidence for β cell neogenesis in murine adult pancreas
Whether facultative β cell progenitors exist in the adult pancreas is a major unsolved question. To date, lineage-tracing studies have provided conflicting results. To track β cell neogenesis in vivo, we generated transgenic mice that transiently coexpress mTomato and GFP in a time-sensitive, nonconditional Cre-mediated manner, so that insulin-producing cells express GFP under control of the insulin promoter, while all other cells express mTomato (INS Cre mTmG mice). Newly differentiated β cells were detected by flow cytometry and fluorescence microscopy, taking advantage of their transient coexpression of GFP and mTomato fluorescent proteins. We found that β cell neogenesis predominantly occurs during embryogenesis, decreases dramatically shortly after birth, and is completely absent in adults across various models of β cell loss, β cell growth and regeneration, and inflammation. Moreover, we demonstrated upregulation of neurogenin 3 (NGN3) in both proliferating ducts and preexisting β cells in the ligated pancreatic tail after pancreatic ductal ligation. These results are consistent with some recent reports, but argue against the widely held belief that NGN3 marks cells undergoing endocrine neogenesis in the pancreas. Our data suggest that β cell neogenesis in the adult pancreas occurs rarely, if ever, under either normal or pathological conditions.
Stem Cells, 2009
Embryonic stem (ES) cells represent a possible source of islet tissue for the treatment of diabetes. Achieving this goal will require a detailed understanding of how the transcription factor cascade initiated by the homeodomain transcription factor Pdx1 culminates in pancreatic β-cell development. Here we describe a genetic approach that enables fine control of Pdx1 transcriptional activity during endoderm differentiation of mouse and human ES cell. By activating an exogenous Pdx1VP16 protein in populations of cells enriched in definitive endoderm we show a distinct lineage-dependent requirement for this transcription factor's activity. Mimicking the natural biphasic pattern of Pdx1 expression was necessary to induce an endocrine pancreas-like cell phenotype, in which 30% of the cells were β-cell-like. Cell markers consistent with the different β-cell differentiation stages appeared in a sequential order following the natural pattern of pancreatic development. Furthermore, in mo...
Development
To gain a deeper understanding of pancreatic β-cell development, we used iterative weighted gene correlation network analysis to calculate a gene co-expression network (GCN) from 11 temporally and genetically defined murine cell populations. The GCN, which contained 91 distinct modules, was then used to gain three new biological insights. First, we found that the clustered protocadherin genes are differentially expressed during pancreas development. Pcdhγ genes are preferentially expressed in pancreatic endoderm, Pcdhβ genes in nascent islets, and Pcdhα genes in mature β-cells. Second, after extracting sub-networks of transcriptional regulators for each developmental stage, we identified 81 zinc finger protein (ZFP) genes that are preferentially expressed during endocrine specification and β-cell maturation. Third, we used the GCN to select three ZFPs for further analysis by CRISPR mutagenesis of mice. Zfp800 null mice exhibited early postnatal lethality, and at E18.5 their pancreat...
The International Journal of Developmental Biology, 2005
Insulin-producing cells derived from embryonic stem cells could be surrogates for beta cells in diabetes therapy. However, their derivation remains hard to achieve with current protocols which rely on initial embryoid body formation. We assume that factors known to inhibit pancreas development contribute to this limitation in vitro. To evaluate this hypothesis, embryoid bodies were examined after different culture periods by real time RT-PCR to profile the expression of genes known to regulate embryonic pancreas development. Our data indicate that transcripts for pancreas markers (insulin, glucagon and amylase ) were expressed during differentiation, but the highest levels achieved were at least 10 5 times lower than in the adult mouse pancreas. Notch signalling was activated as suggested by Delta, Jagged, Ngn3 and NeuroD1 profiles. However, Sonic hedgehog, a known inhibitor of pancreas induction in vivo drastically increased in day 6 embryoid bodies, while Inhibin βA and βB were down-regulated and follistatin up-regulated.
Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas
Nature Medicine, 2006
The nature and even existence of adult pancreatic endocrine stem or progenitor cells is a subject of controversy in the field of beta-cell replacement for diabetes. One place to search for such cells is in the nonendocrine fraction of cells that remain after islet isolation, which consist of a mixture of epithelia and mesenchyme. Culture in G418 resulted in elimination of the mesenchymal cells, leaving a highly purified population of nonendocrine pancreatic epithelial cells (NEPECs). To evaluate their differentiation potential, NEPECs were heritably marked and transplanted under the kidney capsule of immunodeficient mice. When cotransplanted with fetal pancreatic cells, NEPECs were capable of endocrine differentiation. We found no evidence of beta-cell replication or cell fusion that could have explained the appearance of insulin positive cells from a source other than NEPECs. Nonendocrine-to-endocrine differentiation of NEPECs supports the existence of endocrine stem or progenitor cells within the epithelial compartment of the adult human pancreas.