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Juliana Guimarães Zulian, Larissa Yukari Massarenti Hosoya, Priscila Moreira Figueiredo, Daniela Ogias, Luciana Harumi Osaki, Patricia Gama
Gastric epithelial cells differentiate throughout the third postnatal week in rats, and become completely functional by weaning time. When suckling is interrupted by early weaning (EW), cell proliferation and differentiation change in the gastric mucosa, and regulatory mechanisms might involve corticosterone activity. Here we used EW and RU486 (glucocorticoid receptor antagonist) to investigate the roles of corticosterone on differentiation of mucous neck (MNC) and zymogenic cells (ZC) in rats, and to evaluate whether effects persisted in young adults...
March 31, 2017: Scientific Reports
Hei-Yong G Lo, Ramon U Jin, Greg Sibbel, Dengqun Liu, Anju Karki, Matthew S Joens, Blair B Madison, Bo Zhang, Valerie Blanc, James A J Fitzpatrick, Nicholas O Davidson, Stephen F Konieczny, Jason C Mills
We hypothesized that basic helix-loop-helix (bHLH) MIST1 (BHLHA15) is a "scaling factor" that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules...
January 15, 2017: Genes & Development
Padma Pradeepa Srinivasan, Vaishali N Patel, Shuang Liu, Daniel A Harrington, Matthew P Hoffman, Xinqiao Jia, Robert L Witt, Mary C Farach-Carson, Swati Pradhan-Bhatt
Radiotherapy for head and neck cancer often has undesirable effects on salivary glands that lead to xerostomia or severe dry mouth, which can increase oral infections. Our goal is to engineer functional, three-dimensional (3D) salivary gland neotissue for autologous implantation to provide permanent relief. An immediate need exists to obtain autologous adult progenitor cells as the use of embryonic and induced pluripotent stem cells potentially pose serious risks such as teratogenicity and immunogenic rejection...
January 2017: Stem Cells Translational Medicine
Andrew D Shubin, Timothy J Felong, Brittany E Schutrum, Debria S L Joe, Catherine E Ovitt, Danielle S W Benoit
Radiation therapy for head and neck cancers leads to permanent xerostomia due to the loss of secretory acinar cells in the salivary glands. Regenerative treatments utilizing primary submandibular gland (SMG) cells show modest improvements in salivary secretory function, but there is limited evidence of salivary gland regeneration. We have recently shown that poly(ethylene glycol) (PEG) hydrogels can support the survival and proliferation of SMG cells as multicellular spheres in vitro. To further develop this approach for cell-based salivary gland regeneration, we have investigated how different modes of PEG hydrogel degradation affect the proliferation, cell-specific gene expression, and epithelial morphology within encapsulated salivary gland spheres...
March 1, 2017: Acta Biomaterialia
Victoria G Weis, Christine P Petersen, Jared A Weis, Anne R Meyer, Eunyoung Choi, Jason C Mills, James R Goldenring
The plasticity of gastric chief cells is exemplified by their ability to transdifferentiate into spasmolytic polypeptide-expressing metaplasia (SPEM) after parietal cell loss. We sought to determine if chief cell maturity is a limiting factor in the capacity to transdifferentiate. Mist1(-)(/-) mice, previously shown to form only immature chief cells, were treated with DMP-777 or L635 to study the capability of these immature chief cells to transdifferentiate into a proliferative metaplastic lineage after acute parietal cell loss...
January 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
Mei Jiang, Ana Azevedo-Pouly, Tye G Deering, Chinh Q Hoang, Daniel DiRenzo, David A Hess, Stephen F Konieczny, Galvin H Swift, Raymond J MacDonald
Much remains unknown regarding the regulatory networks formed by transcription factors in mature, differentiated mammalian cells in vivo, despite many studies of individual DNA-binding transcription factors. We report a constellation of feed-forward loops formed by the pancreatic transcription factors MIST1 and PTF1 that govern the differentiated phenotype of the adult pancreatic acinar cell. PTF1 is an atypical basic helix-loop-helix transcription factor complex of pancreatic acinar cells and critical to acinar cell fate specification and differentiation...
September 19, 2016: Molecular and Cellular Biology
David A Hess, Katherine M Strelau, Anju Karki, Mei Jiang, Ana C Azevedo-Pouly, Ann-Hwee Lee, Tye G Deering, Chinh Q Hoang, Raymond J MacDonald, Stephen F Konieczny
Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator...
September 19, 2016: Molecular and Cellular Biology
Padma Pradeepa Srinivasan, Vaishali N Patel, Shuang Liu, Daniel A Harrington, Matthew P Hoffman, Xinqiao Jia, Robert L Witt, Mary C Farach-Carson, Swati Pradhan-Bhatt
: Radiotherapy for head and neck cancer often has undesirable effects on salivary glands that lead to xerostomia or severe dry mouth, which can increase oral infections. Our goal is to engineer functional, three-dimensional (3D) salivary gland neotissue for autologous implantation to provide permanent relief. An immediate need exists to obtain autologous adult progenitor cells as the use of embryonic and induced pluripotent stem cells potentially pose serious risks such as teratogenicity and immunogenic rejection...
August 18, 2016: Stem Cells Translational Medicine
Benjamin D Moore, Shradha S Khurana, Won Jae Huh, Jason C Mills
We have previously shown that the sequential transcription factors Xbp1→Mist1 (Bhlha15) govern the ultrastructural maturation of the secretory apparatus in enzyme-secreting zymogenic chief cells (ZCs) in the gastric unit. Here we sought to identify transcriptional regulators upstream of X-box binding protein 1 (XBP1) and MIST1. We used immunohistochemistry to characterize Hnf4α(flox/flox) adult mouse stomachs after tamoxifen-induced deletion of Hnf4α We used qRT-PCR, Western blotting, and chromatin immunoprecipitation to define the molecular interaction between hepatocyte nuclear factor 4 alpha (HNF4α) and Xbp1 in mouse stomach and human gastric cells...
August 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Eunyoung Choi, Audrey M Hendley, Jennifer M Bailey, Steven D Leach, James R Goldenring
BACKGROUND & AIMS: Gastric cancer develops in the context of parietal cell loss, spasmolytic polypeptide-expressing metaplasia (SPEM), and intestinal metaplasia (IM). We investigated whether expression of the activated form of Ras in gastric chief cells of mice leads to the development of SPEM, as well as progression of metaplasia. METHODS: We studied Mist1-CreERT2Tg/+;LSL-K-Ras(G12D)Tg/+ (Mist1-Kras) mice, which express the active form of Kras in chief cells on tamoxifen exposure...
April 2016: Gastroenterology
J M Bailey, A M Hendley, K J Lafaro, M A Pruski, N C Jones, J Alsina, M Younes, A Maitra, F McAllister, C A Iacobuzio-Donahue, S D Leach
Pancreatic cancer is one of the most lethal malignancies, with virtually all patients eventually succumbing to their disease. Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53(R172H) using Hnf1b:CreER(T2) and Mist1:CreER(T2) mice. These studies involved co-activation of a membrane-tethered GFP lineage label, allowing for direct visualization and isolation of cells undergoing Kras and mutant p53 activation...
August 11, 2016: Oncogene
Yoku Hayakawa, Hiroshi Ariyama, Jitka Stancikova, Kosuke Sakitani, Samuel Asfaha, Bernhard W Renz, Zinaida A Dubeykovskaya, Wataru Shibata, Hongshan Wang, Christoph B Westphalen, Xiaowei Chen, Yoshihiro Takemoto, Woosook Kim, Shradha S Khurana, Yagnesh Tailor, Karan Nagar, Hiroyuki Tomita, Akira Hara, Antonia R Sepulveda, Wanda Setlik, Michael D Gershon, Subhrajit Saha, Lei Ding, Zeli Shen, James G Fox, Richard A Friedman, Stephen F Konieczny, Daniel L Worthley, Vladimir Korinek, Timothy C Wang
The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1(+) stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12(+) endothelial cells and Cxcr4(+) gastric innate lymphoid cells (ILCs)...
December 14, 2015: Cancer Cell
Hiromi Chikada, Keiichi Ito, Ayaka Yanagida, Hiromitsu Nakauchi, Akihide Kamiya
Hepatic stem/progenitor cells, hepatoblasts, have a high proliferative ability and can differentiate into mature hepatocytes and cholangiocytes. Therefore, these cells are considered to be useful for regenerative medicine and drug screening for liver diseases. However, it is problem that in vitro maturation of hepatoblasts is insufficient in the present culture system. In this study, a novel regulator to induce hepatic differentiation was identified and the molecular function of this factor was examined in embryonic day 13 hepatoblast culture with maturation factor, oncostatin M and extracellular matrices...
2015: Scientific Reports
Dachuan Qi, Bo Wu, Danian Tong, Ye Pan, Wei Chen
The current study aimed to isolate key transcription factors (TFs) in caerulein-induced pancreatitis, and to identify the difference between wild type and Mist1 knockout (KO) mice, in order to elucidate the contribution of Mist1 to pancreatitis. The gene profile of GSE3644 was downloaded from the Gene Expression Omnibus database then analyzed using the t-test. The isolated differentially expressed genes (DEGs) were mapped into a transcriptional regulatory network derived from the Integrated Transcription Factor Platform database and in the network, the interaction pairs involving at least one DEG were screened...
August 2015: Molecular Medicine Reports
Melissa A Metzler, Srirangapatnam G Venkatesh, Jaganathan Lakshmanan, Anne L Carenbauer, Sara M Perez, Sarah A Andres, Savitri Appana, Guy N Brock, James L Wittliff, Douglas S Darling
OBJECTIVE: The transcription factor networks that drive parotid salivary gland progenitor cells to terminally differentiate, remain largely unknown and are vital to understanding the regeneration process. METHODOLOGY: A systems biology approach was taken to measure mRNA and microRNA expression in vivo across acinar cell terminal differentiation in the rat parotid salivary gland. Laser capture microdissection (LCM) was used to specifically isolate acinar cell RNA at times spanning the month-long period of parotid differentiation...
2015: PloS One
Marit H Aure, Stephen F Konieczny, Catherine E Ovitt
Current dogma suggests that salivary gland homeostasis is stem cell dependent. However, the extent of stem cell contribution to salivary gland maintenance has not been determined. We investigated acinar cell replacement during homeostasis, growth, and regeneration, using an inducible CreER(T2) expressed under the control of the Mist1 gene locus. Genetic labeling, followed by a chase period, showed that acinar cell replacement is not driven by the differentiation of unlabeled stem cells. Analysis using R26(Brainbow2...
April 20, 2015: Developmental Cell
Andrew D Shubin, Timothy J Felong, Dean Graunke, Catherine E Ovitt, Danielle S W Benoit
More than 40,000 patients are diagnosed with head and neck cancers annually in the United States with the vast majority receiving radiation therapy. Salivary glands are irreparably damaged by radiation therapy resulting in xerostomia, which severely affects patient quality of life. Cell-based therapies have shown some promise in mouse models of radiation-induced xerostomia, but they suffer from insufficient and inconsistent gland regeneration and accompanying secretory function. To aid in the development of regenerative therapies, poly(ethylene glycol) hydrogels were investigated for the encapsulation of primary submandibular gland (SMG) cells for tissue engineering applications...
June 2015: Tissue Engineering. Part A
Kelsey F Andersen, Laurence V Madden, Pierce A Paul
Mist chamber experiments were conducted to quantify and model the effects of post-anthesis moisture on Fusarium head blight (FHB) index (IND) and deoxynivalenol (DON). Four mist treatments, one daily and three intermittent, were applied during an 8-day window immediately after anthesis, plus an untreated check. All intermittent mist treatments received moisture on 4 of the 8 days, but the distribution of the supplemental moisture during the treatment window varied among the treatments. Separate sets of spikes in each treatment were either spray or point inoculated with a spore suspension of Fusarium graminearum...
February 2015: Phytopathology
Michael A Hale, Galvin H Swift, Chinh Q Hoang, Tye G Deering, Toshi Masui, Youn-Kyoung Lee, Jumin Xue, Raymond J MacDonald
The orphan nuclear receptor NR5A2 is necessary for the stem-like properties of the epiblast of the pre-gastrulation embryo and for cellular and physiological homeostasis of endoderm-derived organs postnatally. Using conditional gene inactivation, we show that Nr5a2 also plays crucial regulatory roles during organogenesis. During the formation of the pancreas, Nr5a2 is necessary for the expansion of the nascent pancreatic epithelium, for the subsequent formation of the multipotent progenitor cell (MPC) population that gives rise to pre-acinar cells and bipotent cells with ductal and islet endocrine potential, and for the formation and differentiation of acinar cells...
August 2014: Development
Charis L Johnson, Rashid Mehmood, Scott W Laing, Camilla V Stepniak, Alexei Kharitonenkov, Christopher L Pin
Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism under conditions of stress such as starvation, obesity, and hypothermia. Rapid induction of FGF21 is also observed in experimental models of pancreatitis, and FGF21 reduces tissue damage observed in these models, suggesting a nonmetabolic function. Pancreatitis is a debilitating disease with significant morbidity that greatly increases the risk of pancreatic ductal adenocarcinoma. The goals of this study were to examine the regulation and function of FGF21 in acinar cell injury, specifically in a mouse model of pancreatic injury (Mist1(-/-))...
April 15, 2014: American Journal of Physiology. Endocrinology and Metabolism
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