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

Internal Medicine
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 in homeostasis, regeneration, and tumorigenesis. 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, Drosophila genetics, H pylori infections, 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.

Recently, using multiple mammalian tissues, coupled with Drosophila genetic and tissue-based approaches, we have determined that mature cells use a conserved program to become regenerative in response to large-scale damage. Because the genes and pathways involved in turning a mature cell into a progenitor-like cell seem to be conserved across tissues and species, we propose that there is a conserved molecular program for this type of reprogramming, similar to how cells, independent of tissue and species, have a shared program for division (mitosis) and death (eg, apoptosis). We call this program paligenosis from pali (return) + genes (to a regenerative state). Paligenosis involves retooling the cell`s metabolic program using changes in mTORC1 and other pathways and genes from its normal adult function to transform into a proliferating cell that can repair damage. Currently, our lab is studying the conserved genes (akin to caspases for apoptosis and cyclins for mitosis) that govern paligenosis.

Selected Publications:

Willet SG, Lewis MA, Miao ZF, Liu D, Radyk MD, Cunningham RL, Burclaff J, Sibbel G, Lo HG, Blanc V, Davidson NO, Wang ZN, Mills JC. Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J. (2018) 37: e98311. :PMC5881627

Radyk MD, Burclaff J, Willet SG, Mills JC. Metaplastic cells in the stomach arise, independently of stem cells, via dedifferentiation or transdifferentiation of chief cells. Gastroenterology. (2018) 154:839-843. PMC5847468

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. PMC5391042

Burclaff J, Mills JC. Cell biology: Healthy skin rejects cancer. (2017) Nature. 548:289-290

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.

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

Last Updated: 7/27/2018 11:11:36 AM

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