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Human duodenal submucosal glands contain a defined stem/progenitor subpopulation with liver-specific regenerative potential

Published:September 08, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.037

      Highlights

      • Endodermal progenitors are present in the submucosal glands of adult human duodenum.
      • Duodenal submucosal gland cells can be isolated from adult human duodenum.
      • Duodenal submucosal gland cells can acquire hepatocyte functional traits in vitro.
      • Duodenal submucosal gland cells rescue liver damage in murine chronic liver injury.

      Background & Aims

      Common precursors for the liver, biliary tree, and pancreas exist at an early stage of development in the definitive endoderm forming the foregut. We have identified and characterised endodermal stem/progenitor cells with regenerative potential persisting in the adult human duodenum.

      Methods

      Human duodena were obtained from organ donors, and duodenal submucosal gland cells were isolated after removal of the mucosa layer. Cells were cultured on plastic or as organoids and were transplanted into severe combined immunodeficient (SCID) mouse livers.

      Results

      In situ studies of submucosal glands in the human duodenum revealed cells expressing stem/progenitor cell markers that had unique phenotypic traits distinguishable from intestinal crypt cells. Genetic signature studies indicated that the cells are closer to biliary tree stem cells and to definitive endodermal cells than to adult hepatocytes, supporting the interpretation that they are endodermal stem/progenitor cells. In vitro, human duodenal submucosal gland cells demonstrated clonal growth, capability to form organoids, and ability to acquire functional hepatocyte traits. In vivo, transplanted cells engrafted into the livers of immunocompromised mice and differentiated to mature liver cells. In an experimental model of fatty liver, human duodenal submucosal gland cells were able to rescue hosts from liver damage by supporting repopulation and regeneration of the liver.

      Conclusions

      A cell population with clonal growth and organoid formation capability, which has liver differentiation potency in vitro and in vivo in murine experimental models, is present within adult duodenal submucosal glands. These cells can be isolated, do not require reprogramming, and thus could potentially represent a novel cell source for regenerative medicine of the liver.

      Impact and implications

      Cell therapies for liver disease could represent an option to support liver function, but the identification of sustainable and viable cell sources is critical. Here, we describe a cell population with organoid formation capability and liver-specific regenerative potential in submucosal glands of the human duodenum. Duodenal submucosal gland cells are isolated from adult organs, do not require reprogramming, and could rescue hepatocellular damage in preclinical models of chronic, but not acute, liver injury. Duodenal submucosal gland cells could represent a potential candidate cell source for regenerative medicine of the liver, but the determination of cell dose and toxicity is needed before clinical testing in humans.

      Graphical abstract

      Keywords

      Linked Article

      • New cell-based approaches for liver disorders: From experimental to validated clinical treatment
        Journal of HepatologyVol. 78Issue 1
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          The year 1992 is widely considered “year zero” for liver cell-based treatments in humans. It was December 1992 when the first clinical report was published, describing an autologous cell-based approach for 10 individuals with end-stage cirrhosis in Japan.1 It was still 1992 when Drs Strom and Fisher used allogeneic hepatocytes to rescue a patient with fulminant hepatitis for the first time.2 This early success led to the development of similar treatments for both acute and congenital liver disorders in subsequent years.
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