Jason C. Mills, M.D., Ph.D.

Professor
Internal Medicine
Gastroenterology
Developmental Biology

Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program
Immunology Program

  • 314-362-4213

  • 314-362-4258

  • 314-362-7487

  • 8124

  • 927 Clinical Sciences Research Building, North Tower

  • jmills@wustl.edu

  • http://millslab.wustl.edu

  • cancer, differentiation, functional genomics, pathogenesis, stem cells, transcriptional regulation

  • Developmental, molecular, and cellular biology of gastrointestinal epithelial stem cells and gastric cancer

Research Abstract:

My lab is using a multipronged approach to understand the cellular and molecular details of adult stem cell biology in the mouse and human GI tract. We are interested both in normal developmental pathways from the multipotent stem cell and in uncovering the aberrations that occur when those pathways go awry (e.g., in stomach and pancreatic cancer). In particular, we are focusing on how the gastric epithelium has both a constitutively active stem cell that increases proliferation following injury and an inducible stem stem cell, which is the digestive-enzyme-secreting (zymogenic) chief cell. The chief cell is normally post-mitotic, but, in response to injury/inflammation, it can scale down its elaborate digestive-enzyme-secreting cellular apparatus and re-enter the cell cycle. In humans, infection with Helicobacter pylori can cause this downscaling and proliferation with the result being that the stomach undergoes metaplasia. We combine mouse genetics, human histopathology and bioinformatic promoter/expression analyses, as well as in vitro mechanistic studies to identify the genes involved in both the metaplastic normal stem cell response as well as the reprogramming of the chief cell. For example, the bHLH transcription factor Mist1, required for normal maturation of zymogenic cells, is lost during the dedifferentiation of these cells.

Making a chief cell from a stem cell requires scaling up the secretory apparatus, and reprogramming a chief cell back into a stem cell requires scaling it down again. Thus, we have been particularly interested in transcription factors like MIST1, which we have termed Scaling Factors and that allow mature cells to increase or decrease specific, functional subcellular programs. For example, gastric zymogenic cells and bone marrow plasma cells arise via entirely different cellular lineages and don`t secrete the same substances, yet they both require the transcription factor XBP1 to reach structural maturity. XBP1 directly induces the elaborate ER these specialized secretory cells need to produce and release large volumes of protein. XBP1 also directly activates MIST1, which induces vesicular trafficking machinery to further increase secretory function. To study how assembly of specialized organelles, such as abundant lamellar rough endoplasmic reticulum and large secretory granules, can be coordinated at the transcriptional level, we are identifying the molecular targets of MIST1 and determining what role each of these plays in constructing the secretory apparatus.

Selected Publications:

Burclaff J, Osaki LH, Liu D, Goldenring JR, Mills JC. Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach. (2017)Gastroenterology, 152:762-766

Lo HG, Jin RU, Sibbel G, Liu D, Karki A, Joens MS, Madison BB, Zhang B, Blanc V, Fitzpatrick JA...Mills JC. A single transcription factor is sufficient to induce and maintain secretory cell architecture. (2017) Genes Dev, 31:1154-171

Sáenz JB, Mills JC Biological techniques: stomach growth in a dish (2017) Nature 541:160-161.

Moore BD, Jin RU, Lo H, Jung M, Wang H, Battle MA, Wollheim CB, Urano F, Mills JC. (2016) Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function. J Biol Chem, 291:6146-6157.

Mills JC, Sansom OJ. (2015) Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract. Sci Signal, 8(385):re8.

Stange DE, Koo B-K, Huch M, Sibbel G, Basak O, Lyubimova A, Kujala P, Bartfeld S, Koster J, Geahlen JH, Peters PJ, van Es JH, van de Wetering M, Mills JC, Clevers H. (2013) Differentiated Troy+ chief cells acta as “reserve” stem cells to generate all lineages of the stomach epithelium. Cell, 155:357-368

Khurana SS, Riehl TE, Moore BD, Fassan M, Rugge M, Romero-Gallo J, Noto J, Peek RM, Stenson WF, Mills JC. (2013) The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation. J Biol Chem, 288:16085-16097. PMCID: PMC3668764 (chosen for cover illustration)

Capoccia BJ, Jin RU, Kong Y-Y, Peek RM Jr, Fassan M, Rugge M, Mills JC. (2013) The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation. J Clin Invest, 123:1474-1491. PMCID: 3613919

Mills JC, Shivdasani RA (2011) Gastric epithelial stem cells. Gastroenterology 140:412-424.PMCID: PMC3708552

Huh WJ, Esen E, Geahlen JH, Bredemeyer AJ, Lee AH, Shi G, Konieczny SF, Glimcher LH, Mills JC. (2010) XBP1 controls maturation of gastric zymogenic cells by induction of MIST1 and expansion of the rough endoplasmic reticulum. Gastroenterology, 139:2038-2049. PMCID: PMC2997137

Last Updated: 6/14/2017 4:40:44 PM

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