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JOURNAL ARTICLE
Marina Lizio, Yuri Ishizu, Masayoshi Itoh, Timo Lassmann, Akira Hasegawa, Atsutaka Kubosaki, Jessica Severin, Hideya Kawaji, Yukio Nakamura, Harukazu Suzuki, Yoshihide Hayashizaki, Piero Carninci, Alistair R R Forrest
Mammals are composed of hundreds of different cell types with specialized functions. Each of these cellular phenotypes are controlled by different combinations of transcription factors. Using a human non islet cell insulinoma cell line (TC-YIK) which expresses insulin and the majority of known pancreatic beta cell specific genes as an example, we describe a general approach to identify key cell-type-specific transcription factors (TFs) and their direct and indirect targets. By ranking all human TFs by their level of enriched expression in TC-YIK relative to a broad collection of samples (FANTOM5), we confirmed known key regulators of pancreatic function and development...
2015: Frontiers in Genetics
#22
JOURNAL ARTICLE
Sergiu Şuşman, Dan Rus-Ciucă, Olga Soriţău, Răzvan Ciortea, Mihai Gîrlovanu, Dan Mihu, Carmen Mihaela Mihu
OBJECTIVES: The apparition of sugar diabetes is produced by the decrease of the number and capacity of beta cells to secrete insulin. Cell mass recovery through cell therapy might be one of the solutions for treating this disease. The use of various cell sources of different differentiation grades has been tried over the last years. Decoding the molecular mechanisms of the pancreatic morphogenesis is essential for obtaining cells having a phenotype, which would be very similar to the mature cells located in the pancreatic endocrine component...
2015: Romanian Journal of Morphology and Embryology
#23
JOURNAL ARTICLE
Ling Chen, Jing Zhang, Zhuo Zhang, Yaping Chu, Bing Song, Wang Cai
BACKGROUND/AIMS: The lack of available beta cells greatly limits the use of beta cell transplantation as a therapy for diabetes. Thus, generation of beta cells from other sources is substantially required. Pax4 has been shown to induce reprograming of alpha cells into beta cells during embryogenesis. Nevertheless, whether expression of Pax4 in adult alpha cells could trigger this alpha-to-beta cell reprogramming is unknown. METHODS: Here we generated an adeno-associated virus carrying Pax4 and GFP under a CMV promoter (AAV-Pax4)...
2015: Cellular Physiology and Biochemistry
#24
REVIEW
Prabhu Mathiyalagan, Samuel T Keating, Keith Al-Hasani, Assam El-Osta
SIGNIFICANCE: Type 1 diabetes (T1D) results from cell-mediated autoimmune destruction of insulin-secreting pancreatic beta cells (β-cells). In the context of T1D, the scarcity of organ donors has driven research to alternate sources of functionally competent, insulin-secreting β-cells as substitute for donor islets to meet the clinical need for transplantation therapy. RECENT ADVANCES: Experimental evidence of an inherent plasticity of pancreatic cells has fuelled interest in in vivo regeneration of β-cells...
June 1, 2015: Antioxidants & Redox Signaling
#25
JOURNAL ARTICLE
Caroline B Sangan, Ramiro Jover, Harry Heimberg, David Tosh
There is currently a shortage of organ donors available for pancreatic beta cell transplantation into diabetic patients. An alternative source of beta cells is pre-existing pancreatic cells. While we know that beta cells can arise directly from alpha cells during pancreatic regeneration we do not understand the molecular basis for the switch in phenotype. The aim of the present study was to investigate if hepatocyte nuclear factor 4 alpha (HNF4α), a transcription factor essential for a normal beta cell phenotype, could induce the reprogramming of alpha cells towards potential beta cells...
January 5, 2015: Molecular and Cellular Endocrinology
#26
JOURNAL ARTICLE
Jennifer R Kulzer, Michael L Stitzel, Mario A Morken, Jeroen R Huyghe, Christian Fuchsberger, Johanna Kuusisto, Markku Laakso, Michael Boehnke, Francis S Collins, Karen L Mohlke
Genome-wide association studies (GWASs) have identified more than 70 loci associated with type 2 diabetes (T2D), but for most, the underlying causal variants, associated genes, and functional mechanisms remain unknown. At a T2D- and fasting-proinsulin-associated locus on 11q13.4, we have identified a functional regulatory DNA variant, a candidate target gene, and a plausible underlying molecular mechanism. Fine mapping, conditional analyses, and exome array genotyping in 8,635 individuals from the Metabolic Syndrome in Men study confirmed a single major association signal between fasting proinsulin and noncoding variants (p = 7...
February 6, 2014: American Journal of Human Genetics
#27
JOURNAL ARTICLE
Anahita Shaer, Negar Azarpira, Akbar Vahdati, Mohammad Hosein Karimi, Mehrdad Shariati
OBJECTIVES: In diabetes mellitus type 1, beta cells are mostly destroyed; while in diabetes mellitus type 2, beta cells are reduced by 40% to 60%. We hope that soon, stem cells can be used in diabetes therapy via pancreatic beta cell replacement. Induced pluripotent stem cells are a kind of stem cell taken from an adult somatic cell by "stimulating" certain genes. These induced pluripotent stem cells may be a promising source of cell therapy. This study sought to produce isletlike clusters of insulin-producing cells taken from induced pluripotent stem cells...
February 2015: Experimental and Clinical Transplantation
#28
JOURNAL ARTICLE
Blair K Gage, Travis D Webber, Timothy J Kieffer
Human embryonic stem cells (hESCs) have the ability to form cells derived from all three germ layers, and as such have received significant attention as a possible source for insulin-secreting pancreatic beta-cells for diabetes treatment. While considerable advances have been made in generating hESC-derived insulin-producing cells, to date in vitro-derived glucose-responsive beta-cells have remained an elusive goal. With the objective of increasing the in vitro formation of pancreatic endocrine cells, we examined the effect of varying initial cell seeding density from 1...
2013: PloS One
#29
JOURNAL ARTICLE
Rémy Bonnavion, Rami Jaafar, Julie Kerr-Conte, Fouzia Assade, Esther van Stralen, Emmanuelle Leteurtre, Célio Pouponnot, Sofia Gargani, François Pattou, Philippe Bertolino, Martine Cordier-Bussat, Jieli Lu, Chang Xian Zhang
Pax4 and MafA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A) are two transcription factors crucial for normal functions of islet beta cells in the mouse. Intriguingly, recent studies indicate the existence of notable difference between human and rodent islet in terms of gene expression and functions. To better understand the biological role of human PAX4 and MAFA, we investigated their expression in normal and diseased human islets, using validated antibodies. PAX4 was detected in 43.0±5.0% and 39...
2013: PloS One
#30
JOURNAL ARTICLE
Sudhanshu P Raikwar, Nicholas Zavazava
Pluripotent embryonic stem (ES) cells and induced pluripotent stem (iPS) cells recently developed in our laboratory can be used to generate the much needed insulin producing cells (IPCs) for the treatment of type 1 diabetes. However, currently available differentiation protocols generate IPCs at a very low frequency. More importantly, it is difficult to purify the IPCs from the mixed cell population due to the lack of well characterized pancreatic beta cell-specific cell surface markers. Subsequently, multiple studies have been published with limited success...
2013: Methods in Molecular Biology
#31
JOURNAL ARTICLE
R C W Ma, C Hu, C H Tam, R Zhang, P Kwan, T F Leung, G N Thomas, M J Go, K Hara, X Sim, J S K Ho, C Wang, H Li, L Lu, Y Wang, J W Li, Y Wang, V K L Lam, J Wang, W Yu, Y J Kim, D P Ng, H Fujita, K Panoutsopoulou, A G Day-Williams, H M Lee, A C W Ng, Y-J Fang, A P S Kong, F Jiang, X Ma, X Hou, S Tang, J Lu, T Yamauchi, S K W Tsui, J Woo, P C Leung, X Zhang, N L S Tang, H Y Sy, J Liu, T Y Wong, J Y Lee, S Maeda, G Xu, S S Cherny, T F Chan, M C Y Ng, K Xiang, A P Morris, S Keildson, R Hu, L Ji, X Lin, Y S Cho, T Kadowaki, E S Tai, E Zeggini, M I McCarthy, K L Hon, L Baum, B Tomlinson, W Y So, Y Bao, J C N Chan, W Jia
AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations...
June 2013: Diabetologia
#32
JOURNAL ARTICLE
Qing Le Liang, Zhengying Mo, Xue Feng Li, Xiao Xun Wang, Rui Ming Li
Success in generating insulin-producing cells (IPCs) from human embryonic stem (hES) cells by genetic manipulation has recently revealed a new therapeutic potential for diabetes. However, clinical application has been hampered by the viral genome integration and the risk of insertion mutagenesis that are entailed. Herein, we report the induction of hEC into IPCs by direct delivery of human Pdx1 proteins per se. Recombinant human Pdx1 proteins (hPdx1), which have an Antennapedia-like protein transduction domain sequence in their structure, can be efficiently translocated into hES cells and function as pancreatic transcription factor...
January 2013: Cell Biology International
#33
JOURNAL ARTICLE
P Rahnamay Moshtagh, S Hojati Emami, Ali M Sharifi
Stem cells with the ability to differentiate into insulin-producing cells (IPCs) are becoming the most promising therapy for diabetes mellitus and reduce the major limitations of availability and allogeneic rejection of beta cell transplantations. Mesenchymal stem cells (MSCs) are pluripotent stromal cells with the ability to proliferate and differentiate into a variety of cell types including endocrine cells of the pancreas. This study sought to inspect the in vitro differentiation of human adipose-derived tissue stem cells into IPCs which could provide an abundant source of cells for the purpose of diabetic cell therapy in addition to avoid immunological rejection...
September 2013: Journal of Physiology and Biochemistry
#34
JOURNAL ARTICLE
Joachim Djiotsa, Vincianne Verbruggen, Jean Giacomotto, Minaka Ishibashi, Elisabeth Manning, Silke Rinkwitz, Isabelle Manfroid, Marianne L Voz, Bernard Peers
BACKGROUND: Genetic studies in mouse have demonstrated the crucial function of PAX4 in pancreatic cell differentiation. This transcription factor specifies β- and δ-cell fate at the expense of α-cell identity by repressing Arx gene expression and ectopic expression of PAX4 in α-cells is sufficient to convert them into β-cells. Surprisingly, no Pax4 orthologous gene can be found in chicken and Xenopus tropicalis raising the question of the function of pax4 gene in lower vertebrates such as in fish...
2012: BMC Developmental Biology
#35
JOURNAL ARTICLE
Dong-Qi Tang, Qiwei Wang, Brant R Burkhardt, Sally A Litherland, Mark A Atkinson, Li-Jun Yang
Efforts involving therapeutic islet cell transplantation have been hampered by limited islet availability and immune rejection. In vitro transdifferentiation of human bone marrow-derived stem (hBMDS) cells into functional insulin-producing cells promises to provide a tissue source for autologous cell transplantation. In this study, we isolated hBMDS cells, developed a single-cell-derived stem cell line, and induced the cells to differentiate into islet-like clusters. These islet-like cells expressed multiple genes related to islet development and beta cell function (e...
June 30, 2012: American Journal of Stem Cells
#36
JOURNAL ARTICLE
Simon Kordowich, Palle Serup, Patrick Collombat, Ahmed Mansouri
Pax4 belongs to the paired-box family of transcription factors. The analysis of loss- and gain-of-function mutant animals revealed that this factor plays a crucial role in the endocrine pancreas. Indeed, Pax4 is required for the genesis of insulin-producing beta-cells. Remarkably, the sole misexpression of Pax4 in glucagon-expressing cells is able to induce their regeneration, endow these with beta-cell features, and thereby counter chemically induced diabetes. However, the function of Pax4 in adult endocrine cells remains unclear...
December 2012: Transgenic Research
#37
JOURNAL ARTICLE
Hana Segev, Betina Fishman, Rita Schulman, Joseph Itskovitz-Eldor
Even before the first appearance of the developing pancreas, glucose is the major substrate in the growing embryo. The transport of glucose across cell membranes is facilitated by a family of membranal glucose transporters (GLUT). We analyzed changes in expression of class 1 glucose transporters (GLUT1-4) during human embryonic stem cell (hESC) and human induced pluripotent stem cell (hiPSC) differentiation, from undifferentiated cells to 28-day-old embryoid bodies (EBs). We also examined the potential use of GLUT2 as a marker for differentiating pancreatic progenitor cells...
July 1, 2012: Stem Cells and Development
#38
JOURNAL ARTICLE
Yoon Shin Cho, Chien-Hsiun Chen, Cheng Hu, Jirong Long, Rick Twee Hee Ong, Xueling Sim, Fumihiko Takeuchi, Ying Wu, Min Jin Go, Toshimasa Yamauchi, Yi-Cheng Chang, Soo Heon Kwak, Ronald C W Ma, Ken Yamamoto, Linda S Adair, Tin Aung, Qiuyin Cai, Li-Ching Chang, Yuan-Tsong Chen, Yutang Gao, Frank B Hu, Hyung-Lae Kim, Sangsoo Kim, Young Jin Kim, Jeannette Jen-Mai Lee, Nanette R Lee, Yun Li, Jian Jun Liu, Wei Lu, Jiro Nakamura, Eitaro Nakashima, Daniel Peng-Keat Ng, Wan Ting Tay, Fuu-Jen Tsai, Tien Yin Wong, Mitsuhiro Yokota, Wei Zheng, Rong Zhang, Congrong Wang, Wing Yee So, Keizo Ohnaka, Hiroshi Ikegami, Kazuo Hara, Young Min Cho, Nam H Cho, Tien-Jyun Chang, Yuqian Bao, Åsa K Hedman, Andrew P Morris, Mark I McCarthy, Ryoichi Takayanagi, Kyong Soo Park, Weiping Jia, Lee-Ming Chuang, Juliana C N Chan, Shiro Maeda, Takashi Kadowaki, Jong-Young Lee, Jer-Yuarn Wu, Yik Ying Teo, E Shyong Tai, Xiao Ou Shu, Karen L Mohlke, Norihiro Kato, Bok-Ghee Han, Mark Seielstad
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3...
December 11, 2011: Nature Genetics
#39
JOURNAL ARTICLE
Simon Kordowich, Patrick Collombat, Ahmed Mansouri, Palle Serup
BACKGROUND: Nkx2.2 and Arx represent key transcription factors implicated in the specification of islet cell subtypes during pancreas development. Mice deficient for Arx do not develop any alpha-cells whereas beta- and delta-cells are found in considerably higher numbers. In Nkx2.2 mutant animals, alpha- and beta-cell development is severely impaired whereas a ghrelin-expressing cell population is found augmented.Notably, Arx transcription is clearly enhanced in Nkx2.2-deficient pancreata...
August 31, 2011: BMC Developmental Biology
#40
JOURNAL ARTICLE
Vikash Chandra, G Swetha, Sudhakar Muthyala, Amit K Jaiswal, Jayesh R Bellare, Prabha D Nair, Ramesh R Bhonde
BACKGROUND: Type 1 Diabetes Mellitus is caused by auto immune destruction of insulin producing beta cells in the pancreas. Currently available treatments include transplantation of isolated islets from donor pancreas to the patient. However, this method is limited by inadequate means of immuno-suppression to prevent islet rejection and importantly, limited supply of islets for transplantation. Autologous adult stem cells are now considered for cell replacement therapy in diabetes as it has the potential to generate neo-islets which are genetically part of the treated individual...
2011: PloS One
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