Transdifferentiation of pancreatic ductal cells to endocrine β-cells

2008 ◽  
Vol 36 (3) ◽  
pp. 353-356 ◽  
Author(s):  
Susan Bonner-Weir ◽  
Akari Inada ◽  
Shigeru Yatoh ◽  
Wan-Chun Li ◽  
Tandy Aye ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Duct Cell ◽  
Cell Types ◽  
Lineage Tracing ◽  
Β Cells ◽  
Partial Pancreatectomy ◽  
Pancreatic Cell ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells

The regenerative process in the pancreas is of particular interest, since diabetes, whether Type 1 or Type 2, results from an inadequate amount of insulin-producing β-cells. Islet neogenesis, or the formation of new islets, seen as budding of hormone-positive cells from the ductal epithelium, has long been considered to be one of the mechanisms of normal islet growth after birth and in regeneration, and suggested the presence of pancreatic stem cells. Results from the rat regeneration model of partial pancreatectomy led us to hypothesize that differentiated pancreatic ductal cells were the pancreatic progenitors after birth, and that with replication they regressed to a less differentiated phenotype and then could differentiate to form new acini and islets. There are numerous supportive results for this hypothesis of neogenesis, including the ability of purified primary human ducts to form insulin-positive cells budding from ducts. However, to rigorously test this hypothesis, we took a direct approach of genetically marking ductal cells using CAII (carbonic anhydrase II) as a duct-cell-specific promoter to drive Cre recombinase in lineage-tracing experiments using the Cre-Lox system. We show that CAII-expressing pancreatic cells act as progenitors that give rise to both new islets and acini after birth and after injury (ductal ligation). This identification of a differentiated pancreatic cell type as an in vivo progenitor for all differentiated pancreatic cell types has implications for a potential expandable source for new islets for replenishment therapy for diabetes either in vivo or ex vivo.

scholarly journals Intraislet Pancreatic Ducts Can Give Rise to Insulin-Positive Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (1) ◽  
pp. 166-175 ◽  
Author(s):  
Yousef El-Gohary ◽  
John Wiersch ◽  
Sidhartha Tulachan ◽  
Xiangwei Xiao ◽  
Ping Guo ◽  
...  
Keyword(s):  
Lineage Tracing ◽  
Mutant Mice ◽  
Pancreatic Ducts ◽  
Diabetes Research ◽  
Wild Type ◽  
Β Cells ◽  
Partial Pancreatectomy ◽  
Ductal Cells ◽  
Adult Mice ◽  
Pancreatic Ductal Cells

Abstract A key question in diabetes research is whether new β-cells can be derived from endogenous, nonendocrine cells. The potential for pancreatic ductal cells to convert into β-cells is a highly debated issue. To date, it remains unclear what anatomical process would result in duct-derived cells coming to exist within preexisting islets. We used a whole-mount technique to directly visualize the pancreatic ductal network in young wild-type mice, young humans, and wild-type and transgenic mice after partial pancreatectomy. Pancreatic ductal networks, originating from the main ductal tree, were found to reside deep within islets in young mice and humans but not in mature mice or humans. These networks were also not present in normal adult mice after partial pancreatectomy, but TGF-β receptor mutant mice demonstrated formation of these intraislet duct structures after partial pancreatectomy. Genetic and viral lineage tracings were used to determine whether endocrine cells were derived from pancreatic ducts. Lineage tracing confirmed that pancreatic ductal cells can typically convert into new β-cells in normal young developing mice as well as in adult TGF-β signaling mutant mice after partial pancreatectomy. Here the direct visual evidence of ducts growing into islets, along with lineage tracing, not only represents strong evidence for duct cells giving rise to β-cells in the postnatal pancreas but also importantly implicates TGF-β signaling in this process.

scholarly journals Establishment of human pluripotent stem cell-derived pancreatic β-like cells in the mouse pancreas

2018 ◽  
Vol 115 (15) ◽  
pp. 3924-3929 ◽  
Author(s):  
Haiting Ma ◽  
Katherine J. Wert ◽  
Dmitry Shvartsman ◽  
Douglas A. Melton ◽  
Rudolf Jaenisch
Keyword(s):  
Stem Cell ◽  
Cell Types ◽  
Human Cells ◽  
Β Cells ◽  
Orthotopic Transplantation ◽  
In Vivo Models ◽  
Pancreatic Cell ◽  
Mouse Pancreas ◽  
Ductal Cells ◽  
Neonatal Mice

Type 1 diabetes is characterized by autoimmune destruction of β cells located in pancreatic islets. However, tractable in vivo models of human pancreatic β cells have been limited. Here, we generated xenogeneic human pancreatic β-like cells in the mouse pancreas by orthotopic transplantation of stem cell-derived β (SC-β) cells into the pancreas of neonatal mice. The engrafted β-like cells expressed β cell transcription factors and markers associated with functional maturity. Engrafted human cells recruited mouse endothelial cells, suggesting functional integration. Human insulin was detected in the blood circulation of transplanted mice for months after transplantation and increased upon glucose stimulation. In addition to β-like cells, human cells expressing markers for other endocrine pancreas cell types, acinar cells, and pancreatic ductal cells were identified in the pancreata of transplanted mice, indicating that this approach allows studying other human pancreatic cell types in the mouse pancreas. Our results demonstrate that orthotopic transplantation of human SC-β cells into neonatal mice is an experimental platform that allows the generation of mice with human pancreatic β-like cells in the endogenous niche.

scholarly journals The stromal cell–derived factor-1α/CXCR4 ligand–receptor axis is critical for progenitor survival and migration in the pancreas

2003 ◽  
Vol 163 (4) ◽  
pp. 859-869 ◽  
Author(s):  
Ayse G. Kayali ◽  
Kurt Van Gunst ◽  
Iain L. Campbell ◽  
Aleksandr Stotland ◽  
Marcie Kritzik ◽  
...  
Keyword(s):  
Duct Cell ◽  
Cell Types ◽  
Diabetic Mouse ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Cells ◽  
Nonobese Diabetic ◽  
Pancreatic Ductal Cells ◽  
Stromal Cell Derived Factor ◽  
And Migration ◽  
Nonobese Diabetic Mice

The SDF-1α/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1α and CXCR4 expression in fetal pancreas. We have found that SDF-1α and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) γ–nonobese diabetic mouse. We show that SDF-1α stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1α on ductal cell migration. Importantly, blocking the SDF-1α/CXCR4 axis in IFNγ-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1α–CXCR4 ligand receptor axis is an obligatory component in the maintenance of duct cell survival, proliferation, and migration during pancreatic regeneration.

Cellular plasticity of the pancreas

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Luc Baeyens ◽  
Luc Bouwens
Keyword(s):  
Diabetes Mellitus ◽  
Cell Differentiation ◽  
Cell Types ◽  
Β Cells ◽  
Cell Replacement Therapy ◽  
Β Cell ◽  
Pancreatic Cell ◽  
Cell Replacement

Abstract Cell replacement therapy holds promises for treatment of patients suffering from diabetes mellitus. When determining the appropriate strategies to amplify the amount of transplantable β-cells, sufficient knowledge of the developmental programs regulating β-cell differentiation is crucial. Here, we describe the plasticity of the different pancreatic cell types in vivo and in vitro and their potential to serve as β-cell progenitor.

Ductal Cell Reprogramming to Insulin-Producing Beta-Like Cells as a Potential Beta Cell Replacement Source for Chronic Pancreatitis

2019 ◽  
Vol 14 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Aravinth P. Jawahar ◽  
Siddharth Narayanan ◽  
Gopalakrishnan Loganathan ◽  
Jithu Pradeep ◽  
Gary C. Vitale ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Beta Cell ◽  
Lineage Tracing ◽  
Clinical Tool ◽  
Glucose Levels ◽  
Ductal Cells ◽  
Pancreatic Ductal Cells ◽  
Insulin Producing Cells ◽  
Ductal Cell ◽  
Recent Advances

Islet cell auto-transplantation is a novel strategy for maintaining blood glucose levels and improving the quality of life in patients with chronic pancreatitis (CP). Despite the many recent advances associated with this therapy, obtaining a good yield of islet infusate still remains a pressing challenge. Reprogramming technology, by making use of the pancreatic exocrine compartment, can open the possibility of generating novel insulin-producing cells. Several lineage-tracing studies present evidence that exocrine cells undergo dedifferentiation into a progenitor-like state from which they can be manipulated to form insulin-producing cells. This review will present an overview of recent reports that demonstrate the potential of utilizing pancreatic ductal cells (PDCs) for reprogramming into insulin- producing cells, focusing on the recent advances and the conflicting views. A large pool of ductal cells is released along with islets during the human islet isolation process, but these cells are separated from the pure islets during the purification process. By identifying and improving existing ductal cell culture methods and developing a better understanding of mechanisms by which these cells can be manipulated to form hormone-producing islet-like cells, PDCs could prove to be a strong clinical tool in providing an alternative beta cell source, thus helping CP patients maintain their long-term glucose levels.

scholarly journals Protocol for in vivo and ex vivo assessments of glucose-stimulated insulin secretion in mouse islet β cells

2021 ◽  
Vol 2 (3) ◽  
pp. 100728
Author(s):  
Yun-Xia Zhu ◽  
Yun-Cai Zhou ◽  
Yan Zhang ◽  
Peng Sun ◽  
Xiao-Ai Chang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ex Vivo ◽  
Β Cells ◽  
Mouse Islet ◽  
Glucose Stimulated Insulin Secretion

scholarly journals Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo

2010 ◽  
Vol 298 (4) ◽  
pp. E807-E814 ◽  
Author(s):  
Lara R. Nyman ◽  
Eric Ford ◽  
Alvin C. Powers ◽  
David W. Piston
Keyword(s):  
Blood Flow ◽  
Blood Glucose ◽  
Pancreatic Islets ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Cell Types ◽  
Β Cells ◽  
Islet Blood Flow ◽  
Significant Difference

Pancreatic islets are highly vascularized and arranged so that regions containing β-cells are distinct from those containing other cell types. Although islet blood flow has been studied extensively, little is known about the dynamics of islet blood flow during hypoglycemia or hyperglycemia. To investigate changes in islet blood flow as a function of blood glucose level, we clamped blood glucose sequentially at hyperglycemic (∼300 mg/dl or 16.8 mM) and hypoglycemic (∼50 mg/dl or 2.8 mM) levels while simultaneously imaging intraislet blood flow in mouse models that express green fluorescent protein in the β-cells or yellow fluorescent protein in the α-cells. Using line scanning confocal microscopy, in vivo blood flow was assayed after intravenous injection of fluorescent dextran or sulforhodamine-labeled red blood cells. Regardless of the sequence of hypoglycemia and hyperglycemia, islet blood flow is faster during hyperglycemia, and apparent blood volume is greater during hyperglycemia than during hypoglycemia. However, there is no change in the order of perfusion of different islet endocrine cell types in hypoglycemia compared with hyperglycemia, with the islet core of β-cells usually perfused first. In contrast to the results in islets, there was no significant difference in flow rate in the exocrine pancreas during hyperglycemia compared with hypoglycemia. These results indicate that glucose differentially regulates blood flow in the pancreatic islet vasculature independently of blood flow in the rest of the pancreas.

scholarly journals In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1483
Author(s):  
Emily A. Bates ◽  
John R. Counsell ◽  
Sophie Alizert ◽  
Alexander T. Baker ◽  
Natalie Suff ◽  
...  
Keyword(s):  
Viral Vector ◽  
Ex Vivo ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Types ◽  
In Vivo Evaluation ◽  
In Vivo Biodistribution ◽  
Adenovirus Type 5

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.

Abstract 290: Haemogenic Endocardium Contribute To Definitive Hematopoiesis During Cardiogenesis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Haruko Nakano ◽  
Xiaoqian Liu ◽  
Armin Arshi ◽  
Ben van Handel ◽  
Rajkumar Sasidharan ◽  
...  
Keyword(s):  
De Novo ◽  
Ex Vivo ◽  
Embryonic Stem ◽  
Circulatory System ◽  
Lineage Tracing ◽  
Mouse Heart ◽  
Heart Tube ◽  
Cardiac Progenitors ◽  
Definitive Hematopoiesis

The circulatory system is the first functional organ system that develops during mammalian life. Accumulating evidences suggest that cardiac and endocardial cells can arise from a single common progenitor cell during mammalian cardiogenesis. Notably, these early cardiac progenitors express multiple hematopoietic transcription factors, consistent with previous reports. Indeed, a close relationship among cardiac, endocardial and hematopoietic lineages has been suggested in fly, zebrafish, and embryonic stem cell in vitro differentiation models. However, it is unclear when, where and how this hematopoietic gene program is in operation during in vivo mammalian cardiogenesis. Hematopoietic colony assay suggests that mouse heart explants generate myeloids and erythroids in the absence of circulation, suggesting that the heart tube is a de novo site for the definitive hematopoiesis. Lineage tracing revealed that putative cardiac-derived Nkx2-5+/Isl1+ endocardial cells give rise to CD41+ hematopoietic progenitors that contribute to definitive hematopoiesis in vivo and ex vivo during embryogenesis earlier than in the AGM region. Furthermore, Nkx2-5 and Isl1 are both required for the hemogenic activity of the endocardium. Together, identification of Nkx2-5/Isl1-dependent hemogenic endocardial cells (1) adds hematopoietic component in the cardiogenesis lineage tree, (2) changes the long-held dogma that AGM is the only major source of definitive hematopoiesis in the embryo proper, and (3) represents phylogenetically conserved fundamental mechanism of cardio-vasculo-hematopoietic differentiation pathway during the development of circulatory system.

scholarly journals The interplay of osteogenesis and hematopoiesis

2004 ◽  
Vol 167 (6) ◽  
pp. 1113-1122 ◽  
Author(s):  
Sergei A. Kuznetsov ◽  
Mara Riminucci ◽  
Navid Ziran ◽  
Takeo W. Tsutsui ◽  
Alessandro Corsi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Parathyroid Hormone ◽  
Ex Vivo ◽  
Cell Types ◽  
Heterotopic Bone ◽  
Stromal Compartment ◽  
Marrow Space ◽  
Stromal Tissue

The ontogeny of bone marrow and its stromal compartment, which is generated from skeletal stem/progenitor cells, was investigated in vivo and ex vivo in mice expressing constitutively active parathyroid hormone/parathyroid hormone–related peptide receptor (PTH/PTHrP; caPPR) under the control of the 2.3-kb bone-specific mouse Col1A1 promoter/enhancer. The transgene promoted increased bone formation within prospective marrow space, but delayed the transition from bone to bone marrow during growth, the formation of marrow cavities, and the appearance of stromal cell types such as marrow adipocytes and cells supporting hematopoiesis. This phenotype resolved spontaneously over time, leading to the establishment of marrow containing a greatly reduced number of clonogenic stromal cells. Proliferative osteoprogenitors, but not multipotent skeletal stem cells (mesenchymal stem cells), capable of generating a complete heterotopic bone organ upon in vivo transplantation were assayable in the bone marrow of caPPR mice. Thus, PTH/PTHrP signaling is a major regulator of the ontogeny of the bone marrow and its stromal tissue, and of the skeletal stem cell compartment.

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