Beta cell neogenesis from ducts and phenotypic conversion of residual islet cells in the adult pancreas of glucose intolerant mice induced by selective alloxan perfusion.
ABSTRACT The aim of this study was to clarify the pattern of beta cell neogenesis in the alloxan-perfused, beta cells-depleted segment of glucose intolerant mice induced by selective alloxan perfusion. First, duct cells proliferated in the perfused segment, then cells co-expressing multiple islet hormones and transcription factors such as PDX-1, Nkx2.2, Isl1, and Pax6 were observed in duct cells, and newly formed islet-like cell clusters (ICCs) containing beta cells were recognized. In residual beta cell-depleted islets, glucagon or somatostatin and PDX-1 double-positive immature endocrine cells were recognized. Glucagon or somatostatin, insulin and PDX-1 triple-positive cells then appeared and these cells appeared to undergo terminal differentiation into beta cells. In conclusion, we demonstrated at least two different processes of beta cell neogenesis, i.e., formation of new ICCs from ductal epithelium and redifferentiation of residual non-beta islet cells in this model. In addition, transcription factors that appear in the processes of endocrine cell development may also play essential roles during beta cell neogenesis from duct cells.
- SourceAvailable from: Patrick Collombat[Show abstract] [Hide abstract]
ABSTRACT: The pancreas is composed of two main compartments consisting of endocrine and exocrine tissues. The majority of the organ is exocrine and responsible for the synthesis of digestive enzymes and for their transport via an intricate ductal system into the duodenum. The endocrine tissue represents less than 2% of the organ and is organized into functional units called islets of Langerhans, comprising alpha-, beta-, delta-, epsilon- and PP-cells, producing the hormones glucagon, insulin, somatostatin, ghrelin and pancreatic polypeptide (PP), respectively. Insulin-producing beta-cells play a central role in the control of the glucose homeostasis. Accordingly, absolute or relative deficiency in beta-cells may ultimately lead to type 1 and/or type 2 diabetes, respectively. One major goal of diabetes research is therefore to understand the molecular mechanisms controlling the development of beta-cells during pancreas morphogenesis, but also those underlying the regeneration of adult injured pancreas, and assess their significance for future cell-based therapy. In this review, we will therefore present new insights into beta-cell development with focus on beta-cell regeneration.Seminars in Cell and Developmental Biology 10/2010; 21(8):838-44. · 6.20 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The pancreas is composed of two compartments that deliver digestive enzymes and endocrine hormones to control the blood sugar level. The endocrine pancreas consists of functional units organized into cell clusters called islets of Langerhans where insulin-producing cells are found in the core and surrounded by glucagon-, somatostatin-, pancreatic polypeptide-, and ghrelin-producing cells. Diabetes is a devastating disease provoked by the depletion or malfunction of insulin-producing beta-cells in the endocrine pancreas. The side effects of diabetes are multiple, including cardiovascular, neuropathological, and kidney diseases. The analyses of transgenic and knockout mice gave major insights into the molecular mechanisms controlling endocrine pancreas genesis. Moreover, the study of animal models of pancreas injury revealed that the pancreas has the propensity to undergo regeneration and opened new avenues to develop novel therapeutic approaches for the treatment of diabetes. Thus, beside self-replication of preexisting insulin-producing cells, several potential cell sources in the adult pancreas were suggested to contribute to beta-cell regeneration, including acinar, intraislet, and duct epithelia. However, regeneration in the adult endocrine pancreas is still under controversial debate.ISRN endocrinology. 01/2012; 2012:640956.
Article: Transplantation and beyond[Show abstract] [Hide abstract]
ABSTRACT: The pathophysiology of diabetes, either type 1 or type 2, involves the loss of β cell mass to a point where there is insufficient insulin secretion to meet the body's needs. The overall loss of β cells results from β cell destruction in conjunction with a failure of physiological regulators to restore or regenerate the β cell population. Historically, therapy for diabetes has been limited to efforts to control hyperglycemia and to prevent and/or ameliorate the complications associated with diabetes. Multiple approaches to repopulate the diabetic pancreas with functional islets have been proposed, including whole pancreas transplantation with or without a kidney, direct islet transplantation from cadaveric donors, generation of artificial islets, and development of new islets from stem cells. Ex vivo differentiation of embryonic stem cells offers great attraction as an alternative islet source but, to date, fully functional islets have not been developed. An alternative approach is to target stem cells present in the adult pancreas. Stimulation of these cells with various factors offers the hope of promoting differentiation to functional islets. Islet neogenesis-associated peptide (INGAP) is one such factor. INGAP treatment has reversed insulin-dependent diabetes in a mouse model. INGAP treatment has elicited production of C-peptide in insulin-dependent diabetic patients. Future approaches may combine INGAP with immunosuppression in an attempt to reverse type 1 diabetes. Drug Dev Res 69:165–176, 2008 © 2008 Wiley-Liss, Inc.Drug Development Research 01/2008; 69(3):165-176. · 0.87 Impact Factor