PMID- 32354994
OWN - NLM
STAT- MEDLINE
DCOM- 20200817
LR  - 20210416
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 117
IP  - 20
DP  - 2020 May 19
TI  - Single-cell resolution analysis of the human pancreatic ductal progenitor cell 
      niche.
PG  - 10876-10887
LID - 10.1073/pnas.1918314117 [doi]
AB  - We have described multipotent progenitor-like cells within the major pancreatic 
      ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface 
      marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A 
      (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here 
      we report the single-cell RNA sequencing (scRNA-seq) of ALK3(bright+)-sorted 
      ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our 
      analysis unveiled the existence of multiple subpopulations along two major axes, 
      one that encompasses a gradient of ductal cell differentiation stages, and 
      another featuring cells with transitional phenotypes toward acinar tissue. A 
      third potential ducto-endocrine axis is revealed upon integration of the 
      ALK3(bright+) dataset with a single-cell whole-pancreas transcriptome. When 
      transplanted into immunodeficient mice, P2RY1(+)/ALK3(bright+) populations 
      (enriched in PDX1(+)/ALK3(+)/CAII(-) cells) differentiate into all pancreatic 
      lineages, including functional beta-cells. This process is accelerated when hosts 
      are treated systemically with an ALK3 agonist. We found PDX1(+)/ALK3(+)/CAII(-) 
      progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of 
      the duration of the disease. Our findings open the door to the pharmacological 
      activation of progenitor cells in situ.
CI  - Copyright (c) 2020 the Author(s). Published by PNAS.
FAU - Qadir, Mirza Muhammad Fahd
AU  - Qadir MMF
AUID- ORCID: 0000-0002-6764-6151
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
AD  - Department of Cell Biology and Anatomy, University of Miami Miller School of 
      Medicine, Miami, FL 33136.
FAU - Alvarez-Cubela, Silvia
AU  - Alvarez-Cubela S
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
FAU - Klein, Dagmar
AU  - Klein D
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
FAU - van Dijk, Jasmijn
AU  - van Dijk J
AD  - Instituut voor Life Science & Technology, Hanze University of Applied Sciences, 
      9747 AS Groningen, The Netherlands.
FAU - Muniz-Anquela, Rocio
AU  - Muniz-Anquela R
AD  - Vrije Universiteit Medisch Centrum School of Medical Sciences, Vrije Universiteit 
      Amsterdam, 1081 HV Amsterdam, The Netherlands.
FAU - Moreno-Hernandez, Yaisa B
AU  - Moreno-Hernandez YB
AUID- ORCID: 0000-0001-9823-4312
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
AD  - Facultad de Medicina, Universidad Francisco de Vitoria, 28223 Madrid, Spain.
FAU - Lanzoni, Giacomo
AU  - Lanzoni G
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
FAU - Sadiq, Saad
AU  - Sadiq S
AD  - Department of Electrical and Computer Engineering, University of Miami, Coral 
      Gables, FL 33146.
FAU - Navarro-Rubio, Belen
AU  - Navarro-Rubio B
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
AD  - Facultad de Medicina, Universidad Francisco de Vitoria, 28223 Madrid, Spain.
FAU - Garcia, Michael T
AU  - Garcia MT
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
FAU - Diaz, Angela
AU  - Diaz A
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
FAU - Johnson, Kevin
AU  - Johnson K
AUID- ORCID: 0000-0003-3954-0242
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
FAU - Sant, David
AU  - Sant D
AUID- ORCID: 0000-0001-7372-9896
AD  - Department of Biomedical Informatics, University of Utah, Salt Lake City, UT 
      84108.
FAU - Ricordi, Camillo
AU  - Ricordi C
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136.
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 
      33136.
AD  - Department of Microbiology & Immunology, University of Miami Miller School of 
      Medicine, Miami, FL 33136.
AD  - Department of Biomedical Engineering, University of Miami Miller School of 
      Medicine, Miami, FL 33136.
AD  - Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, 
      University of Miami Miller School of Medicine, Miami, FL 33136.
FAU - Griswold, Anthony
AU  - Griswold A
AD  - The Dr. John T. Macdonald Foundation Department of Human Genetics, John P. 
      Hussman Institute for Human Genomics, University of Miami Miller School of 
      Medicine, Miami, FL 33136.
FAU - Pastori, Ricardo Luis
AU  - Pastori RL
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136; RPastori@med.miami.edu jdominguez2@med.miami.edu.
AD  - The Dr. John T. Macdonald Foundation Department of Human Genetics, John P. 
      Hussman Institute for Human Genomics, University of Miami Miller School of 
      Medicine, Miami, FL 33136.
FAU - Dominguez-Bendala, Juan
AU  - Dominguez-Bendala J
AUID- ORCID: 0000-0001-9410-9143
AD  - Diabetes Research Institute, University of Miami Miller School of Medicine, 
      Miami, FL 33136; RPastori@med.miami.edu jdominguez2@med.miami.edu.
AD  - Department of Cell Biology and Anatomy, University of Miami Miller School of 
      Medicine, Miami, FL 33136.
AD  - Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 
      33136.
LA  - eng
GR  - R43 DK105655/DK/NIDDK NIH HHS/United States
GR  - R44 DK105655/DK/NIDDK NIH HHS/United States
GR  - U01 DK120393/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200430
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (P2RY1 protein, human)
RN  - 0 (Receptors, Purinergic P2Y1)
RN  - 104625-48-1 (Activins)
RN  - EC 2.7.11.30 (BMPR1A protein, human)
RN  - EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type I)
SB  - IM
EIN - Proc Natl Acad Sci U S A. 2021 Feb 9;118(6):. PMID: 33526705
MH  - Activins/metabolism
MH  - Animals
MH  - Bone Morphogenetic Protein Receptors, Type I/metabolism
MH  - Cell Differentiation
MH  - Diabetes Mellitus, Type 1
MH  - Diabetes Mellitus, Type 2
MH  - Female
MH  - Humans
MH  - Insulin-Secreting Cells
MH  - Islets of Langerhans Transplantation
MH  - Male
MH  - Mice
MH  - Models, Animal
MH  - Pancreas/*cytology
MH  - Pancreatic Ducts/*cytology
MH  - Receptors, Purinergic P2Y1/metabolism
MH  - Single-Cell Analysis/*methods
MH  - Stem Cells/*cytology
MH  - Transcriptome
PMC - PMC7245071
OTO - NOTNLM
OT  - human pancreatic progenitors
OT  - islet regeneration
OT  - single-cell RNA sequencing
OT  - transplantation
OT  - type 1 diabetes
COIS- Competing interest statement: The University of Miami and J.D.-B. and C.R. hold, 
      but do not receive royalties for intellectual property used in this study. They 
      are also equity owners in Ophysio, Inc., licensee of the intellectual property.
EDAT- 2020/05/02 06:00
MHDA- 2020/08/18 06:00
PMCR- 2020/04/30
CRDT- 2020/05/02 06:00
PHST- 2020/05/02 06:00 [pubmed]
PHST- 2020/08/18 06:00 [medline]
PHST- 2020/05/02 06:00 [entrez]
PHST- 2020/04/30 00:00 [pmc-release]
AID - 1918314117 [pii]
AID - 201918314 [pii]
AID - 10.1073/pnas.1918314117 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2020 May 19;117(20):10876-10887. doi: 
      10.1073/pnas.1918314117. Epub 2020 Apr 30.