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Kosuke Sakitani, Yoku Hayakawa, Huan Deng, Hiroshi Ariyama, Hiroto Kinoshita, Mitsuru Konishi, Satoshi Ono, Nobumi Suzuki, Sozaburo Ihara, Zhengchuan Niu, Woosook Kim, Takayuki Tanaka, Haibo Liu, Xiaowei Chen, Yagnesh Tailor, James G Fox, Stephen F Konieczny, Hiroshi Onodera, Antonia R Sepulveda, Samuel Asfaha, Yoshihiro Hirata, Daniel L Worthley, Kazuhiko Koike, Timothy C Wang
Mist1 was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express Mist1. The relevance of Mist1 expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using Mist1-CreERT mice, we revealed that Mist1+ antral cells, distinct from the Mist1+ population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above Lgr5+ or CCK2R+ cells...
December 19, 2017: Oncotarget
Yixuan Xia, Hai-Tao Xiao, Kanglun Liu, Hong-Jie Zhang, Siu Wai Tsang
SCOPE: Resveratrol is generally considered beneficial to health-span and longevity since this dietary stilbenoid has been scrutinized for its activating property on the "rescue gene" sirtuin-1 that promotes cellular survival under stress. In addition to its antiaging property, our previous in vitro studies revealed that resveratrol notably inhibited the production of extracellular matrix (ECM) proteins in pancreatic stellate cells (PSCs), the classic effector cells against pancreatic injury...
November 16, 2017: Molecular Nutrition & Food Research
Feeling Y Chen, Albert Lee, Shaokui Ge, Sara Nathan, Sarah M Knox, Nancy A McNamara
Sjögren's syndrome (SS) is a chronic, autoimmune exocrinopathy that leads to severe dryness of the mouth and eyes. Exocrine function is highly regulated by neuronal mechanisms but little is known about the link between chronic inflammation, innervation and altered exocrine function in the diseased eyes and exocrine glands of SS patients. To gain a better understanding of neuronal regulation in the immunopathogenesis of autoimmune exocrinopathy, we profiled a mouse model of spontaneous, autoimmune exocrinopathy that possess key characteristics of peripheral neuropathy experienced by SS patients...
2017: PloS One
K A Metwalli, M A Do, K Nguyen, S Mallick, K Kin, N Farokhnia, G Jun, W D Fakhouri
Interferon regulatory factor 6 ( IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. Haploinsufficiency of IRF6 causes Van der Woude and popliteal pterygium syndrome, 2 syndromic forms of cleft lip and palate. Around 85% of patients with Van der Woude express pits on the lower lip that continuously or intermittently drain saliva, and patients with the common cleft lip and palate have a higher prevalence of dental caries and gingivitis...
September 1, 2017: Journal of Dental Research
Qin Huang, Xiaoping Zou
BACKGROUND: The WHO defines early gastric carcinoma (EGC) as invasive carcinoma up to the submucosal layer, regardless of nodal metastasis. The recent study results indicate that EGC varies in location, histology, nodal metastasis, and prognosis. SUMMARY: The heterogeneity in EGC may be related to various types of epithelial stem cells. The most important stem cells include Lgr5(+) cells at the base of a gastric unit in the antrum-pylorus-cardia, Mist1(+) cells at the isthmus/Troy(+) cells at the base in the corpus-fundus, and Sox2(+) cells at the base in almost all regions...
March 2017: Gastrointestinal Tumors
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
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