Selective effect of INGAP-PP upon mouse embryonic stem cell differentiation toward islet cells
CENEXA - Centro de Endocrinología Experimental y Aplicada (UNLP-CCT La Plata-CONICET, Centro Colaborador de la OPS/OMS), Facultad de Ciencias Médicas Universidad Nacional de La Plata, Argentina.Regulatory Peptides (Impact Factor: 1.83). 02/2009; 153(1-3):43-8. DOI: 10.1016/j.regpep.2008.12.006
We evaluated the effect of islet neogenesis-associated protein pentadecapeptide (INGAP-PP) upon islet beta- and non-beta cell differentiation from mouse embryonic stem (mES) cells. ES-D3 cell lines were cultured following Lumelsky's protocol with or without INGAP-PP (5 microg/ml) at different stages. Gene expression was quantified using qPCR. mES cells were fixed and immunostained using anti insulin-, somatostatin-, glucagon-, Pdx-1-, Ngn-3-, Nkx-6.1 and PGP9.5 specific antibodies. PCNA was used to measure replication rate. Bcl(2) (immunostaining) and caspase-3 (enzyme activity and gene expression) were determined as apoptosis markers. INGAP-PP increased IAPP, Glut-2, Kir-6.2, SUR-1 and insulin gene expression, and the percentage of insulin-immunostained cells. Conversely, INGAP-PP reduced significantly glucagon and somatostatin gene expression and immunopositivity. While nestin gene expression was not affected, there was a significant reduction in the percentage of PGP9.5-immunostained cells. Pdx-1 gene expression increased by 115% in INGAP-PP treated cells, as well as the percentage of Pdx-1, Ngn-3 and Nkx-6.1 immunopositive cells. Neither caspase-3 (expression and activity) nor Bcl(2) positively immunostained cells were affected by INGAP-PP. Accordingly, INGAP-PP would promote stem cell differentiation into a beta-like cell phenotype, simultaneously decreasing its differentiation toward non-beta-cell precursors. Therefore, INGAP-PP would be potentially useful to obtain beta-cells from stem cells for replacement therapy.
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ABSTRACT: Beta-cell replacement is an effective treatment for type 1 diabetes, but its applicability is limited by the lack of sufficient donor tissue, raising the need for alternative tissue sources. Deriving β cells from stem cell precursors offers an unlimited renewable source of tissue for transplantation and in recent years has become the focus of research in many laboratories. The unique state of embryonic stem (ES) cells is characterized by continuous proliferation through a cell cycle consisting of an abbreviated G1 phase. Although this cell cycle exposes ES cells to potential mutations, it also allows continuous culture of undifferentiated cells. Current protocols directing the differentiation of ES cells mimic the normal embryonic development of β cells through definitive endoderm, foregut endoderm, pancreatic precursors, and endocrine progenitor cells. At present all of these steps are suboptimal, since only some of the cells follow this pathway to the intended product. Moral concerns surrounding the use of embryonic stem cells has led to development of alternative sources of pluripotent cells. Current advances in cellular reprogramming are discussed.12/2009: pages 203-220;
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ABSTRACT: The terms "islet" and "β-cell" are often used interchangeably, yet islets are highly complex multicellular organelles that contain the insulin-producing β-cells and four other cells types, all of which play a role in maintaining glucose homeostasis within a very narrow range. Although the formation of new islets in adults is rare, occurring primarily in response to pancreatic injury and major stress to the pancreas, β-cell replication from existing cells occurs throughout adulthood. An understanding of the regulatory factors controlling pancreatic development has more clearly defined the differences between new islet formation from progenitor cells located throughout the adult pancreas and β-cell replication occurring within existing islets. The present review sets forth to more clearly distinguish the differences between the postnatal pathways of islet neogenesis and β-cell replication with a discussion of the potential implications for reversal of Type 1 and 2 diabetic patients using islet neogenesis agents that are now in development. For Type 1 diabetic patients, an immune tolerance agent in conjunction with an islet neogenesis agent may allow achievement of adequate islet mass, perhaps with subsequent potential to withdraw medications. For Type 2 diabetic patients, lifestyle changes and/or medications may sustain the production of new islets and limit the accelerated β-cell apoptosis characteristic of the condition.Journal of Diabetes 06/2010; 2(2):76-84. DOI:10.1111/j.1753-0407.2010.00074.x · 1.93 Impact Factor
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