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
Graphical Abstract
Keywords
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Article info
Publication history
Published online: September 08, 2022
Accepted:
August 23,
2022
Received in revised form:
July 25,
2022
Received:
January 25,
2021
Footnotes
Author names in bold designate shared co-first authorship.
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
