title: The organoid-initiating cells in mouse pancreas and liver are phenotypically and functionally similar.
abstract: Pancreatic Lgr5 expression has been associated with organoid-forming epithelial progenitor populations but the identity of the organoid-initiating epithelial cell subpopulation has remained elusive. Injury causes the emergence of an Lgr5(+) organoid-forming epithelial progenitor population in the adult mouse liver and pancreas. Here, we define the origin of organoid-initiating cells from mouse pancreas and liver prior to Lgr5 activation. This clonogenic population was defined as MIC1-1C3(+)/CD133(+)/CD26(-) in both tissues and the frequency of organoid initiation within this population was approximately 5% in each case. The transcriptomes of these populations overlapped extensively and showed enrichment of epithelial progenitor-associated regulatory genes such as Sox9 and FoxJ1. Surprisingly, pancreatic organoid cells also had the capacity to generate hepatocyte-like cells upon transplantation to Fah(-/-) mice, indicating a differentiation capacity similar to hepatic organoids. Although spontaneous endocrine differentiation of pancreatic progenitors was not observed in culture, adenoviral delivery of fate-specifying factors Pdx1, Neurog3 and MafA induced insulin expression without glucagon or somatostatin. Pancreatic organoid cultures therefore preserve many key attributes of progenitor cells while allowing unlimited expansion, facilitating the study of fate determination.
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Dorrell
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Branden
authors.initials: B
authors.lastname: Tarlow
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Canaday
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Annelise
authors.initials: A
authors.lastname: Haft
authors.affiliation: Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schug
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Streeter
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.affiliation: OHSU Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Lincoln T
authors.initials: LT
authors.lastname: Shenje
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.affiliation: Oregon Stem Cell Center, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: grompem@ohsu.edu.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation; D006867:Hydrolases / Q000172:deficiency / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009940:Organoids / Q000166:cytology / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D015415:Biomarkers; D007328:Insulin; D014157:Transcription Factors; D006867:Hydrolases; C020156:fumarylacetoacetase