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

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.

Informations de copyright

Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Conflicts of interest The authors declare no competing interests, but with the following exceptions. GC, EG, DA, VC, and LMR are inventors on patents on the following: isolation methods and ex vivo maintenance of biliary tree stem cells (US Patent No. US20110135610A1); cryopreservation methods for biliary tree stem cells (US Patent No. US20180295834A1); grafting methods for stem cells (US Patent Nos. 9533013 and 9750770); isolation methods for duodenal submucosal gland cells (US Patent Application 20190300849A1). WZ and LMR are inventors on a patent for patch grafting methods for organoids of stem/progenitors into solid organs (US Patent No. US20180361027A1). The IP is owned by Sapienza University of Rome and/or by the University of North Carolina. The license for the clinical uses in humans is owned by Vesta Therapeutics, and that for the veterinary uses and the non-clinical, commercial uses by PhoenixSongs Biologicals (Branford, CT, USA). None of the authors are employees, receive compensation, or have equity positions in Vesta Therapeutics or PhoenixSongs Biologicals. The exception is LMR, who has a founder’s equity position in PhoenixSongs Biologicals but has received no pay, royalties, or other form of compensation from the company. Please refer to the accompanying ICMJE disclosure forms for further details.