Formation of Pancreatic Duct Epithelium from Bone Marrow During Neonatal Development (original) (raw)
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BMC Developmental Biology, 2010
Background: Histological evidence suggests that insulin-producing beta (β)-cells arise in utero from duct-like structures of the fetal exocrine pancreas, and genetic lineage tracing studies indicate that they are maintained in the adult by self-renewal. These studies have not addressed the origin of the new β-cells that arise in large numbers shortly after birth, and contradictory lineage tracing results have been published regarding the differentiation potential of duct cells in this period. We established an independent approach to address this question directly. Results: We generated mice in which duct and acinar cells, comprising the exocrine pancreas, can be genetically marked by virtue of their expressing the mucin gene Muc1. Using these mice, we performed time-specific lineage tracing to determine if these cells undergo endocrine transdifferentiation in vivo. We find that Muc1 + cells do give rise to β-cells and other islet cells in utero, providing formal proof that mature islets arise from embryonic duct structures. From birth onwards, Muc1 lineage-labeled cells are confined to the exocrine compartment, with no detectable contribution to islet cells. Conclusions: These results argue against a significant contribution by exocrine transdifferentiation to the normal postnatal expansion and maintenance of β-cell mass. Exocrine transdifferentiation has been proposed to occur during injury and regeneration, and our experimental model is suited to test this hypothesis in vivo.
In vivo and in vitro development of mouse pancreatic �-cells in organotypic slices
Cell and Tissue Research, 2004
Taking tissue slices of the embryonic and newborn pancreas is a novel approach for the study of the perinatal development of this gland. The aim of this study was to describe the morphology and physiology of in vivo and in vitro developing b-cells. In addition, we wanted to lay a foundation for the functional analysis of other pancreatic cells, either alone or as part of an integrative pancreatic physiology approach. We used cytochemistry and light microscopy to detect specific markers and the whole-cell patch-clamp to assess the function of single bcells. The insulin signal in the embryonic b-cells was condensed to a subcellular compartment and redistributed throughout the cytosol during the first 2 days after birth. The hormone distribution correlated well with the development of membrane excitability and hormone release competence in b-cells. Endocrine cells survived in the organotypic tissue culture and maintained their physiological properties for weeks. We conclude that our preparation fulfills the criteria for a method of choice to characterize the function of developing pancreas in wildtype and genetically modified mice that die at birth. We suggest organotypic culture for in vitro studies of the development and regeneration of b-cells.
The Bone Marrow as a Potential Receptor Site for Pancreatic Islet Grafts
Archives of Medical Research, 2008
Pancreatic islet transplantation in the human liver is being performed with increasing success to treat diabetes. However, the liver as a receptor site has many drawbacks due to immunological and non-immunological factors as well as important technical limitations. Bone marrow offers an easily accessible extrahepatic receptor site. Therefore, we attempted to explore the survival of pancreatic islets transplanted into the bone marrow of rats. Pancreatic islets islografts and allografts were implanted into the bone marrow of rats. No immunosuppression was used. Morphology, presence of insulin, and glucagon and signs of apoptosis and rejection were explored. Pancreatic islets can be successfully engrafted into the bone marrow of rats, maintaining a normal histological appearance in insulin and glucagon content and no signs of apoptosis or rejection. These preliminary findings suggest that the bone marrow is capable of maintaining pancreatic islets in the absence of immunosuppression and, thus, can constitute an immunoprivileged environment for engraftment.
Diabetes, 1983
The immunofluorescent cell content of the pancreas of 8-40-wk fetuses and of 1.5-5-mo Caucasian infants was quantitatively evaluated using anti-insulin, anti-glicentin, anti-glucagon, anti-somatostatin, and anti-pancreatic polypeptide antisera. The most significant findings are: (1) the pancreas of 8-10 wk fetuses contains a sizable population of endocrine cells reacting exclusively to anti-glicentin antiserum. This cell population decreases and disappears in later stages and is replaced by the adult type glucagon/glicentin immunoreactive cell; (2) the pancreatic polypeptide-rich region shows a lower relative endocrine cell content as compared with the glucagon-rich region and its islets appear smaller; (3) in the total pancreas, the relative (volume density) and absolute (jxl) insulin cell content increases regularly with age, while the relative volume of glucagon cells peaks in fetal life (wk 17-20) to decrease in infants, although remaining at higher levels than in adults; the relative and absolute volumes of somatostatin cells are elevated in fetal and infant stages studied where they represent the second most abundant cell type, while pancreatic polypeptide cells appear the least abundant cells during prenatal and infant life. These data show several differences with the pattern of the respective endocrine cell populations in the adult pancreas. DIABETES 32:293-301, April 1983. R ecently, a quantitative profile of immunofluorescent cell populations (insulin-, glucagon-, somatostatin-, and pancreatic polypeptide-containing cells) was determined in a series of 13 nondiabetic human (Caucasian) adults to establish a baseline for the comparison of pancreatic immunofluorescent cell con
Transplantation Proceedings, 2004
Restrictions in availability of cadaveric human donor pancreata have intensified the search for alternate sources of pancreatic endocrine tissue. We have undertaken to assess whether nonendocrine pancreatic tissue, with special regard to ducts, including epithelial cells, and retrieved from neonatal pig pancreata that are used for islet isolation, may under special in vitro culture conditions generate endocrine cell phenotypes. Special care was taken to identify the time-related appearance of molecular and biochemical markers associated with -cell specificity, in terms of glucose-sensing apparatus and insulin secretion. For this purpose, established ductal origin monolayer cell cultures were incubated with a battery of mono-or polyvalent growth factors. Morphological, immunocytochemical, molecular, and functional assays indicated that under special culture conditions ductal origin cells acquired an endocrine identity, based upon expression of key gene transcripts that govern the stimulus-coupled insulin secretory activity. Among factors eliciting transdifferentiation of ductal epithelial into endocrine cells, Sertoli cell (SC)-conditioned medium seemed to be the most powerful inducer of this process. In fact, the resulting cultures not only expressed -celloriented metabolic markers but also were associated with insulin and C-peptide output at equimolar ratios. This finding indicates that SC coincubation, more than other conditions, caused originally ductal cell cultures to gradually differentiate and mature into -cell-like elements. In vivo studies with this early cell differentiation product will test whether our approach may be suitable for correction of hyperglycemia in diabetic animal models.
Xenotransplantation, 2015
During the process of islet isolation, pancreatic enzymes are activated and released, adversely affecting islet survival and function. We hypothesize that the exocrine component of pancreases harvested from pre-weaned juvenile pigs is immature and hence pancreatic tissue from these donors is protected from injury during isolation and prolonged tissue culture. Biopsy specimens taken from pancreases harvested from neonatal (5-10 days), pre-weaned juvenile (18-22 days), weaned juvenile (45-60 days), and young adult pigs (>90 days) were fixed and stained with hematoxylin and eosin. Sections were examined under a fluorescent microscope to evaluate exocrine zymogen fluorescence intensity (ZFI) and under an electron microscope to evaluate exocrine zymogen granule density (ZGD). Exocrine content estimation showed significantly lower ZFI and ZGD in juvenile pig pancreases (1.5 ± 0.04 U/μm(2) , ZFI; 1.03 ± 0.07 × 10(3) /100 μm(2) , ZGD) compared to young adult pigs (2.4 ± 0.05U/μm(2) , ZFI...
Bone Marrow and Pancreatic Islets: An Old Story With New Perspectives
Cell Transplantation, 2010
In the past years, in the field of β-cell replacement for diabetes therapy, the easy availability of bone marrow (BM) and the widely consolidated clinical experience in the field of hematology have contributed to the development of strategy to achieve donor-specific transplantation tolerance. Recently, the potential role of BM in diabetes therapy has been reassessed from a different point of view. Diverse groups investigated the contribution of BM cells to β-cell replacement as direct differentiation into insulin-producing cells. More importantly, while direct differentiation is highly unlikely, a wide array of experimental evidences indicates that cells of BM origin are capable of facilitating the survival or the endogenous regeneration of β-cells through an as yet well-defined regeneration process. These new experimental in vitro and in vivo data will expand in the near future the clinical trials involving BM or BM-derived cells to cure both type 1 and type 2 diabetes in humans. I...