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Identification of a distinct ductal subpopulation with self-renewal and differentiation potential from the adult murine pancreas

Tremblay, Jacob R. and Ortiz, Jose A. and Quijano, Janine C. and Zook, Heather and LeBon, Jeanne M. and Li, Wendong and Jou, Kevin and Tsark, Walter and Mann, Jeffrey R. and Kozlowski, Mark T. and Tirrell, David A. and Esni, Farzad and Engle, Dannielle D. and Riggs, Arthur D. and Ku, Hsun Teresa (2022) Identification of a distinct ductal subpopulation with self-renewal and differentiation potential from the adult murine pancreas. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20220714-369461000

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Abstract

Pancreatic ducts function to deliver digestive enzymes into the intestines. Upon injury, ducts can become proliferative and contribute to tissue regeneration; however, the identity of the ductal cells that contribute to these processes is unknown. We combined fluorescence-activated cell sorting, a methylcellulose-containing 3-dimensional culture, droplet RNA-sequencing, and a clonal lineage tracing tool to identify and isolate a distinct subpopulation of pancreatic ductal cells that exhibit progenitor cell properties. These ductal cells are unique in that they form tightly-bound clusters (termed FSCmid-high), with an average of 8 cells per cluster. FSCmid-high clusters comprise only about 0.1% of the total pancreas, are tri-potent for duct, acinar and endocrine lineages, and self-renew robustly in vitro. Transcriptomic analysis of FSCmid-high clusters reveals enrichment for genes involved in cell-cell interactions, organ development, and cancer pathways. FSCmid-high clusters express embryonic pancreatic progenitor markers Sox9, Pdx1, and Nkx6-1 at both transcription and protein levels. FSCmid-high clusters are resistant to enzymatic dissociation and survive severe in vivo acinar injury, which induces formation of ductal rosettes that become proliferative within 14 days. Thus, FSCmid-high clusters represent a small subset of ductal cells with progenitor cell properties. These rare progenitor-like duct cell clusters have implications in pancreas regeneration and tumor initiation/progression.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2022.07.12.499653DOIbioRxiv Discussion Paper
https://www.biorxiv.org/content/10.1101/2022.07.12.499653v1.supplementary-materialPublisherSupporting Information
ORCID:
AuthorORCID
Tremblay, Jacob R.0000-0003-1818-7953
Ortiz, Jose A.0000-0002-1688-4299
Quijano, Janine C.0000-0001-7755-3154
Zook, Heather0000-0002-5780-2042
Jou, Kevin0000-0002-9543-9686
Mann, Jeffrey R.0000-0003-0028-8692
Kozlowski, Mark T.0000-0003-4714-8697
Tirrell, David A.0000-0003-3175-4596
Esni, Farzad0000-0002-0342-6862
Engle, Dannielle D.0000-0003-1876-7675
Riggs, Arthur D.0000-0002-8184-5288
Ku, Hsun Teresa0000-0001-5662-9893
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. In memoriam of our beloved colleague Arthur D. Riggs PhD, who passed away during the preparation of this manuscript, we gratefully honor his support and contribution to the current work. We thank Lucy Brown and Alex Spalla for assistance with cell sorting, the integrative genomics core for single-cell RNA-seq analysis, the pathology core for histology analysis, Christiana Crook for technical writing and editing, and Elena C. Chen and Biorender.com for graphic illustration. This work is supported in part by a predoctoral fellowship to J.R.T. from the Norman & Melinda Payson Fellowship at the Irell and Manella Graduate School of Biological Sciences; a predoctoral fellowship to J.O. from the Ford Foundation and from the Helen & Morgan Chu Fellowship at the Irell and Manella Graduate School of Biological Sciences; Juvenile Diabetes Research Foundation postdoctoral fellowship 3PDF2016-174AN and National Pancreas Foundation to J.C.Q.; and National Institutes of Health Grant R01DK099734 to H.T.K. Support from Wanek Family Project of Type 1 Diabetes to H.T.K. is also gratefully acknowledged. Author Contributions: Study Design: J.R.T, J.O. and H.T.K. Data Collection: J.R.T., H.T.K., J.C.Q., J.O., H.Z., J.M.L., W.L. Key Reagents: W.T., M.K., J.R.M., D.A.T., F.E. A.D.R. Data Analysis: J.R.T., H.T.K., J.C.Q., J.O., H.Z., W.L., K.J., W.T., A.D.R. Drafting Paper: J.R.T., J.O., H.T.K., J.C.Q., H.Z., D.D.E., A.D.R. Data Availability. All underlying data is available to interested researchers within reason. Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funders:
Funding AgencyGrant Number
City of HopeUNSPECIFIED
Ford FoundationUNSPECIFIED
Juvenile Diabetes Research Foundation3PDF2016-174AN
National Pancreas FoundationUNSPECIFIED
NIHR01DK099734
Wanek Family Project of Type 1 DiabetesUNSPECIFIED
Subject Keywords:Pancreas, Ductal cells, Progenitor cells, Injury, Proliferation
DOI:10.1101/2022.07.12.499653
Record Number:CaltechAUTHORS:20220714-369461000
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220714-369461000
Official Citation:Identification of a distinct ductal subpopulation with self-renewal and differentiation potential from the adult murine pancreas Jacob R Tremblay, Jose A Ortiz, Janine C Quijano, Heather Zook, Jeanne M LeBon, Wendong Li, Kevin Jou, Walter Tsark, Jeffrey R Mann, Mark Kozlowski, David A Tirrell, Farzad Esni, Dannielle D Engle, Arthur D Riggs, Hsun Teresa Ku bioRxiv 2022.07.12.499653; doi: https://doi.org/10.1101/2022.07.12.499653
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115557
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:15 Jul 2022 22:31
Last Modified:25 Jul 2022 23:13

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