Induced Mist1 Expression Promotes Remodeling of Mouse Pancreatic Acinar Cells

Abstract

BACKGROUND & AIMS Early embryogenesis involves cell fate decisions that define the body axes and establish pools of progenitor cells. Development does not stop once lineages are specified; cells continue to undergo specific maturation events, and changes in gene expression patterns lead to their unique physiological functions. Secretory pancreatic acinar cells mature postnatally to synthesize large amounts of protein, polarize, and communicate with other cells. The transcription factor MIST1 is expressed by only secretory cells and regulates maturation events. MIST1-deficient acinar cells in mice do not establish apical-basal polarity, properly position zymogen granules, or communicate with adjacent cells, disrupting pancreatic function. We investigated whether MIST1 directly induces and maintains the mature phenotype of acinar cells. METHODS We analyzed the effects of Cre-mediated expression of Mist1 in adult Mist1– deficient (Mist1KO) mice. Pancreatic tissues were collected and analyzed by light and electron microscopy, immunohistochemistry, real-time polymerase chain reaction analysis, and chromatin immunoprecipitation. Primary acini were isolated from mice and analyzed in amylase secretion assays. RESULTS Induced expression of Mist1 in adult Mist1KO mice restored wild-type gene expression patterns in acinar cells. The acinar cells changed phenotypes, establishing apical-basal polarity, increasing the size of zymogen granules, reorganizing the cytoskeletal network, communicating intercellularly (by synthesizing gap junctions), and undergoing exocytosis. CONCLUSIONS The exocrine pancreas of adult mice can be remodeled by re-expression of the transcription factor MIST1. MIST1 regulates acinar cell maturation and might be used to repair damaged pancreata in patients with pancreatic disorders.

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

“…Several studies have shown that MIST1 is essential for appropriate responses to diverse cell stimuli, including alcohol and drug-induced inflammation, development, and response to secretagogues (9,10,12,26). Thus, we evaluated if induced Mist1 expression was restricted to ER stress conditions or whether other physiological stresses could influence expression of the Mist1 gene.…”

“…Pancreatic acinar cells lacking MIST1 lose nearly all ability to secrete digestive enzymes and have significantly increased basal cellular autophagy, characteristics that are found under ER stress conditions as well as in cells lacking Xbp1 (12,21,24,49,50). The observed XBP1-mediated induction of Mist1 during ER stress, coupled with the marked reduction in secretion associated with Mist1 KO acinar cells (12,21), prompted us to investigate if MIST1 might regulate a previously uncharacterized set of gene targets needed for both basal and ER stress-induced maintenance of the secretory machinery. For these studies, chromatin from WT mouse pancreata was isolated using two independently derived MIST1 antibodies and subsequently analyzed via ChIP-Seq strategies.…”

“…Acute pancreatitis (AP) was triggered at 7 days postTam administration in adult (6-to 8-week-old) C57BL/6 wild-type, Mist1 cKO (26), and constitutively overexpressing-Mist1 (Mist1 OE ) (12) mice via intraperitoneal injection of caerulein (Sigma-Aldrich, St. Louis, MO) at 50 g/kg body weight in eight hourly injections for two consecutive days. Control mice received phosphate-buffered saline (PBS).…”

“…Secretory cells utilize transcription factor networks to alter their cytoskeletal arrangement, polarity, membrane protein composition, and organelle makeup to support the proper generation, storage, and release of protein products (8). Recently, the basic helix-loop-helix (bHLH) transcription factor MIST1 (encoded by Bhlha15) has emerged as a potent regulator of a wide variety of secretory cell functions and responses to stress (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Secretory cells lacking MIST1 exhibit structural and functional defects, including altered cytoskeletal organization, a change in cell polarity, and improper cell-to-cell communication (12,17,(19)(20)(21).…”

“…Recently, the basic helix-loop-helix (bHLH) transcription factor MIST1 (encoded by Bhlha15) has emerged as a potent regulator of a wide variety of secretory cell functions and responses to stress (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Secretory cells lacking MIST1 exhibit structural and functional defects, including altered cytoskeletal organization, a change in cell polarity, and improper cell-to-cell communication (12,17,(19)(20)(21). Interestingly, the most severe phenotype observed in Mist1 knockout (Mist1 KO ) cells is a nearly complete loss of secretory capacity (21,22), a tantalizing finding that hints at a much more extensive role for MIST1 and its target genes beyond mere regulation of cargo-cytoskeletal interactions.…”