In this study, we employ in vitro models to study the factors involved in the differentiation of pancreatic precursor cells into hormone-producing cells of the islets of Langerhans and their mechanisms of action with a goal to develop a system that could be used for cell replacement therapy for patients with diabetes mellitus. Development of the endocrine pancreas includes a series of early events wherein precursor cells migrate to form aggregates that subsequently differentiate into islets of Langerhans. We use cells derived from human cadaveric pancreata, human islet-derived precursor cells (hIPCs) and CD73/CD90/CD105-positive mesenchymal stem cells (+++MSCs), and a human pancreatic cancer cell line (PANC-1 cells) to study regulation of proliferation, cell migration and aggregation that precede differentiation and differentiation itself. 1) We have now demonstrated that hIPCs are pancreatic MSCs that can differentiate in vitro and in vivo into hormone-expressing cells of the endocrine pancreas. Indeed, we have provided preliminary evidence that bona fide MSCs reside in the pancreas in situ, 2) We showed that hIPCs, and preliminarily +++MSCs, exhibit epigenetic marks that are associated with active gene transcription on the insulin gene even though they are not actively transcribing this gene. This most likely represents a state of commitment for these stem cells to differentiate further to mature endocrine cells. 3) We showed that signaling via the -catenin pathway is critical for proliferation of hIPCs. This pathway may, therefore, be an important target for regulation of the switch from mesenchymal cell proliferation to differentiation to endocrine cells. 4) We showed that the plasminogen/plasmin pathway is capable of regulating PANC-1 cell aggregation that is an early stage in differentiation of these cells into endocrine cells.

Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2008
Total Cost
$603,446
Indirect Cost
City
State
Country
United States
Zip Code
Hiram-Bab, Sahar; Katz, Liora S; Shapira, Hagit et al. (2014) Platelet-derived growth factor BB mimics serum-induced dispersal of pancreatic epithelial cell clusters. J Cell Physiol 229:743-51
Katz, Liora S; Geras-Raaka, Elizabeth; Gershengorn, Marvin C (2013) Reprogramming adult human dermal fibroblasts to islet-like cells by epigenetic modification coupled to transcription factor modulation. Stem Cells Dev 22:2551-60
Couty, Jean-Pierre; Lupu-Meiri, Monica; Oron, Yoram et al. (2009) Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor-expressing endothelial cells exhibit reduced migration and stimulated chemotaxis by chemokine inverse agonists. J Pharmacol Exp Ther 329:1142-7
Ikonomou, L; Geras-Raaka, E; Raaka, B M et al. (2008) Beta-catenin signalling in mesenchymal islet-derived precursor cells. Cell Prolif 41:474-91
Deshet, Naamit; Lupu-Meiri, Monica; Espinoza, Ingrid et al. (2008) Plasminogen-induced aggregation of PANC-1 cells requires conversion to plasmin and is inhibited by endogenous plasminogen activator inhibitor-1. J Cell Physiol 216:632-9
Davani, Behrous; Ikonomou, Laertis; Raaka, Bruce M et al. (2007) Human islet-derived precursor cells are mesenchymal stromal cells that differentiate and mature to hormone-expressing cells in vivo. Stem Cells 25:3215-22
Mutskov, Vesco; Raaka, Bruce M; Felsenfeld, Gary et al. (2007) The human insulin gene displays transcriptionally active epigenetic marks in islet-derived mesenchymal precursor cells in the absence of insulin expression. Stem Cells 25:3223-33
Morton, Russell A; Geras-Raaka, Elizabeth; Wilson, Leah M et al. (2007) Endocrine precursor cells from mouse islets are not generated by epithelial-to-mesenchymal transition of mature beta cells. Mol Cell Endocrinol 270:87-93
Wei, Chiju; Geras-Raaka, Elizabeth; Marcus-Samuels, Bernice et al. (2006) Trypsin and thrombin accelerate aggregation of human endocrine pancreas precursor cells. J Cell Physiol 206:322-8
Gershengorn, Marvin C; Geras-Raaka, Elizabeth; Hardikar, Anandwardhan A et al. (2005) Are better islet cell precursors generated by epithelial-to-mesenchymal transition? Cell Cycle 4:380-2

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