Background & Aims Common precursors for liver, biliary tree and pancreas exist at an early stage of development in the definitive endoderm forming the foregut. We have identified and characterized 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 human duodenum revealed cells expressing stem/progenitor cell markers and with 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 rather than 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, and 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.

Human duodenal submucosal glands contain a defined stem/progenitor subpopulation with liver-specific regenerative potential / V. Cardinale, G. Carpino, D. Overi, S. Safarikia, W. Zhang, M. Kanke, A. Franchitto, D. Costantini, O. Riccioni, L. Nevi, M. Chiappetta, P. Onori, M. Franchitto, S. Bini, Y. Hung, Q. Lai, I. Zizzari, M. Nuti, C. Nicoletti, S. Checquolo, L. Di Magno, M.V. Giuli, M. Rossi, P. Sethupathy, L.M. Reid, D. Alvaro, E. Gaudio. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - (2022). [Epub ahead of print] [10.1016/j.jhep.2022.08.037]

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

L. Nevi;
2022

Abstract

Background & Aims Common precursors for liver, biliary tree and pancreas exist at an early stage of development in the definitive endoderm forming the foregut. We have identified and characterized 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 human duodenum revealed cells expressing stem/progenitor cell markers and with 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 rather than 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, and 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.
cell therapy; duodenum; endoderm; liver; regeneration; stem cells;
Settore MED/09 - Medicina Interna
Settore MED/08 - Anatomia Patologica
Settore BIO/11 - Biologia Molecolare
9-set-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/938926
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