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Islet Transplantation in Type 1 Diabetes: Stem Cell Research and Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
After the pancreatic epithelium growth and proliferation, Notch signaling is inhibited in some epithelial cells, allowing the expression of pro-endocrine gene Neurogenin-3 (Ngn3) [35]. Ngn3 is expressed in all endocrine progenitor cells, which initiates a cascade of transcription factor expression which, in turn, initiates differentiation of endocrine cells. This cascade includes Nkx2-2, Neurod–1, Nkx6-1, Pax6, Pax4, and Isl1.
Endocrine Glands
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Richard A. Peterson, Sundeep Chandra, Mark J. Hoenerhoff
The multiple cell types of the pancreatic islets of Langerhans (pancreatic islets) are incorporated into a “sea” of exocrine pancreatic tissue. In mammals, the endocrine tissue (islets) comprises <5% and the exocrine tissue comprises the remaining >95% of the pancreas. In all mammals, the pancreas is located on the left side of the peritoneal cavity, between the spleen and the pyloric region of the stomach. The pancreas runs along the duodenum and terminates within the mesentery/omentum. The pancreas generally consists of poorly demarcated areas referred to as the body and tail, but there is substantial interspecies variation, and the anatomic terminology varies as well. The distribution and number of islets differ between the areas of the pancreas and between species. During embryonal development, the pancreas arises from the duodenal endoderm (develops into the dorsal that then fuses to form the developing pancreas). The mature pancreas consists primarily of the acinar tissue, which is discussed elsewhere in this book, and the pancreatic islets (Islets of Langerhans), which arise multifocally by budding off of the developing acini and undergo a genetic switch to synthesizing certain protein hormones such as insulin, glucagon, pancreatic polypeptide, ghrelin, and somatostatin (Carlson 1988). The pancreatic islet cells develop through a series of differentiation steps, from primary multipotential progenitor cells that divide to form secondary multipotential precursor cells, which can then differentiate into acinar and bipotential progenitor cells. The bipotential progenitor cells differentiate into ductular cells and endocrine precursor cells. The endocrine precursor cells then undergo a series of cellular divisions and differentiation steps to an endocrine precursor cell, which, depending on the presence of certain transcription factors, will differentiate into α-, δ-, ε-, pancreatic peptide (PP)-, or immature β-cells. Immature β-cells will then differentiate into mature β-cells in the presence of the following transcription factors: Pdx1HI, Mnx1, Nkx6.1, NeuroD, Nkx2.2, MafA, Pax4, Foxa1, and Foxa2 (Pan and Wright 2011).
Regenerating β cells of the pancreas – potential developments in diabetes treatment
Published in Expert Opinion on Biological Therapy, 2018
Indeed, the paired domain containing transcription factor, Pax4, appears to have the capacity to convert α cells into β cells. Studies have shown that Pax4 is mainly expressed in pancreatic islets during embryonic development, and it plays critical roles in the formation of islet cell progenitors and subsequent β- and δ cell differentiation [30,107]. Genetic knockout of Pax4 results in mice without mature β cells or δ cells, but with substantially more α cells [107], demonstrating Pax4 is essential in determining β-cell lineage. This is further confirmed by genetic Pax4 knock-in studies, which have shown forced Pax4 expression in α cells converts them into β cells [108,109]. In humans, Pax4 mutations are found in early-onset T2D patients and maturity-onset diabetes of the young [110–112].
Type 1 diabetes: key drug targets and how they could influence future therapeutics
Published in Expert Opinion on Therapeutic Targets, 2023
Yoon Kook Kim, Kashif M. Munir, Stephen N. Davis
Another potential drug target that focuses on regenerating pancreatic beta cells are the regulatory transcription factors Arx and Pax4, both important in pancreas embryonic development and subsequent islet cell differentiation [47]. Loss of Arx has been shown to induce conversion of pancreatic alpha cells to beta cells in in vitro models [48]. Arx participates in islet cell specialization along with Pax4 by cross-inhibitory interactions and determines the differentiation into alpha or beta islet cells [49]. Down regulation of Arx is thought to promote islet cells to preferentially differentiate into beta cells [50].