Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

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Science Signaling  14 Jul 2015:
Vol. 8, Issue 385, pp. re8
DOI: 10.1126/scisignal.aaa7540
  • Fig. 1 Dedifferentiation, redifferentiation, and metaplasia in the pancreas.

    The figure diagrams how inflammation and tissue damage induce terminally differentiated acinar cells with large, abundant digestive enzyme–containing granules (red) to dedifferentiate to mitotically active tubuloductal structures that coexpress low amounts of digestive enzyme granules along with abundant granules harboring mucins and other regeneration-promoting proteins like osteopontin (yellow). This reprogramming process (i), known as ADM, also involves increased DCLK1-positive cells akin to tuft cells of the luminal GI tract, based on gene expression and morphology. Among others, inflammation, activated KRAS, and signaling by EGFR, YAP, or TNF-α (tumor necrosis factor–α) and RANTES promote ADM; PTEN, TGF-βR2 (transforming growth factor–β receptor 2), Numb, microRNA-495, and Let-7b antagonize progression to ADM. If inflammation resolves, the dedifferentiated cells can redifferentiate to regenerate normal acini; redifferentiation is specifically blocked by IL-6, KRAS, and MEK signaling, or loss of Numb or BMI1. ADM can also persist indefinitely or with accumulation of additional mutations [including activation of Sonic Hedgehog (Shh), loss of p53, TGF-β, or SMAD4], ADM can progress to a form of neoplasia called PDAC (ii). CREDIT: H. MCDONALD/SCIENCE SIGNALING

  • Fig. 2 Proposed stages of reprogramming and metaplasia in the stomach.

    We propose that the first stage of the reprogramming response is for chief cells to “downscale” their secretory architecture [decreasing digestive enzyme–containing granules (red) and dismantling the elaborate rER network (dark blue)]. Cells then reexpress progenitor genes (yellow) with much scanter digestive enzyme granules and are thus, by definition, metaplastic. In the third stage, cells reenter the cell cycle, at which point they may give rise to other metaplasias (like intestinal metaplasia in humans) or progress directly to cancer. In a parallel to pancreatic ADM, metaplastic chief cells may also regenerate other cells again, although much more work needs to be done to determine how commonly this occurs. CREDIT: H. MCDONALD/SCIENCE SIGNALING

  • Fig. 3 Neoplastic growth in the intestines may occur because dedifferentiation of long-lived mature cells unmasks mutations.

    (A) Some of the key cell lineages in the cartoon of one side of a crypt are labeled. (B) Mutations occurring in a crypt base columnar (“CBC”) stem cell may be lost by drift into differentiated cells because CBC cells divide frequently and often symmetrically to produce two daughters that differentiate. Here, we show the daughters differentiating (d, days elapsed). The mutation acquired in the stem cell is lost as the various progeny age and die, except in a long-lived LRC. If the LRC ages and dies without acquiring additional mutations, the original mutation would thence be lost entirely (see also movie S1). (C) However, if, it acquires a second mutation as it ages, both mutations may become unmasked if inflammation that damages the active CBC induces LRCs to dedifferentiate in the presence of high Wnt signaling, leading to proliferation (see also movie S2). The key aspect of this model is that the normal CBC divides too rapidly to accumulate mutations, whereas differentiated cells live longer and can store mutations that may affect proliferation or differentiation but will not affect these quiescent cells until dedifferentiation unmasks them. CREDIT: ADAPTED FROM J.C.M. BY H. MCDONALD/SCIENCE SIGNALING

Supplementary Materials

  • Supplementary Materials for:

    Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

    Jason C. Mills* and Owen J. Sansom*

    *Corresponding author. E-mail: jmills{at} (J.C.M.); o.sansom{at} (O.J.S.)

    This PDF file includes:

    • Legends for movies S1 and S2

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    Technical Details

    Format: Adobe Acrobat PDF

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    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.gif format). Mutation in a stem cell gets stored long term in an LRC.
    • Movie S2 (.gif format). The mutation is unmasked after stem cell damage to fuel an adenoma.

    [Download Movies S1 and S2]

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

    © 2015 American Association for the Advancement of Science

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