Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development

Nadav Sharon; Jordan Vanderhooft; Juerg Straubhaar; Jonas Mueller; Raghav Chawla; Quan Zhou; Elise N. Engquist; Cole Trapnell; David K. Gifford; Douglas A. Melton

doi:10.1016/j.celrep.2019.04.083

Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development

Nadav Sharon
, Jordan Vanderhooft
, Juerg Straubhaar
, Jonas Mueller
, Raghav Chawla
, Quan Zhou
, Elise N. Engquist
, Cole Trapnell
, David K. Gifford
, Douglas A. Melton

Research output: Contribution to journal › Article › peer-review

Abstract

In vitro differentiation of pluripotent cells into β cells is a promising alternative to cadaveric-islet transplantation as a cure for type 1 diabetes (T1D). During the directed differentiation of human embryonic stem cells (hESCS) by exogenous factors, numerous genes that affect the differentiation process are turned on and off autonomously. Manipulating these reactions could increase the efficiency of differentiation and provide a more complete control over the final composition of cell populations. To uncover in vitro autonomous responses, we performed single-cell RNA sequencing on hESCs as they differentiate in spherical clusters. We observed that endocrine cells and their progenitors exist beside one another in separate compartments that activate distinct genetic pathways. WNT pathway inhibition in the endocrine domain of the differentiating clusters reveals a necessary role for the WNT inhibitor APC during islet formation in vivo. Accordingly, WNT inhibition in vitro causes an increase in the proportion of differentiated endocrine cells.

Original language	English
Pages (from-to)	2281-2291.e5
Journal	Cell Reports
Volume	27
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2019.04.083
State	Published - 21 May 2019
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

APC
Single-cell RNA sequencing
WNT pathway
diabetes
hESCs
human embryonic stem cells
in vitro differentiation
insulin
pancreas development
β cells

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2019.04.083

Cite this

@article{40dbfc082a484942a2243cd51bf15e2e,

title = "Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development",

abstract = "In vitro differentiation of pluripotent cells into β cells is a promising alternative to cadaveric-islet transplantation as a cure for type 1 diabetes (T1D). During the directed differentiation of human embryonic stem cells (hESCS) by exogenous factors, numerous genes that affect the differentiation process are turned on and off autonomously. Manipulating these reactions could increase the efficiency of differentiation and provide a more complete control over the final composition of cell populations. To uncover in vitro autonomous responses, we performed single-cell RNA sequencing on hESCs as they differentiate in spherical clusters. We observed that endocrine cells and their progenitors exist beside one another in separate compartments that activate distinct genetic pathways. WNT pathway inhibition in the endocrine domain of the differentiating clusters reveals a necessary role for the WNT inhibitor APC during islet formation in vivo. Accordingly, WNT inhibition in vitro causes an increase in the proportion of differentiated endocrine cells.",

keywords = "APC, Single-cell RNA sequencing, WNT pathway, diabetes, hESCs, human embryonic stem cells, in vitro differentiation, insulin, pancreas development, β cells",

author = "Nadav Sharon and Jordan Vanderhooft and Juerg Straubhaar and Jonas Mueller and Raghav Chawla and Quan Zhou and Engquist, \{Elise N.\} and Cole Trapnell and Gifford, \{David K.\} and Melton, \{Douglas A.\}",

note = "Funding Information: N.S. is partly supported by the Gruss-Lipper Charitable Foundation . D.A.M. is an investigator of the Howard Hughes Medical Institute. This work was supported by grants from the Harvard Stem Cell Institute , Helmsley Charitable Trust and the JPB Foundation . This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (HIRN; RRID: SCR\_014393 , UC4 DK104165 , and UC4 DK104159 ). Funding Information: N.S. is partly supported by the Gruss-Lipper Charitable Foundation. D.A.M. is an investigator of the Howard Hughes Medical Institute. This work was supported by grants from the Harvard Stem Cell Institute, Helmsley Charitable Trust and the JPB Foundation. This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (HIRN; RRID:SCR\_014393, UC4 DK104165, and UC4 DK104159). We thank Prof. Aviv Regev from the Broad Institute and Dr. Alex Shalek, currently at MIT, for help with technical aspects of scRNAseq; and Mrs. Cathy MacGillvary and Mrs. Diane Faria for histological preparations. Conceptualization, N.S. and D.A.M.; Methodology, N.S. J.S. D.G. and D.A.M.; Software, J.S. J.M. R.C. and C.T.; Validation, N.S. J.V. E.N.E. and Q.Z.; Formal Analysis, N.S. J.S. J.M. Q.Z. and E.N.E.; Investigation, N.S. J.V. Q.Z. and E.N.E.; Resources, C.T. D.K.G. and D.A.M.; Data Curation, J.S. R.C. J.M. and C.T.; Writing ? Original Draft, N.S.; Writing ? Review and Editing, N.S. and D.A.M.; Visualization, N.S. J.V. J.S. and Q.Z.; Funding Acquisition, C.T. D.G. and D.A.M. D.A.M. is a founder and SAB member for Semma Therapeutics. Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = may,

day = "21",

doi = "10.1016/j.celrep.2019.04.083",

language = "English",

volume = "27",

pages = "2281--2291.e5",

journal = "Cell Reports",

issn = "2211-1247",

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TY - JOUR

T1 - Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development

AU - Sharon, Nadav

AU - Vanderhooft, Jordan

AU - Straubhaar, Juerg

AU - Mueller, Jonas

AU - Chawla, Raghav

AU - Zhou, Quan

AU - Engquist, Elise N.

AU - Trapnell, Cole

AU - Gifford, David K.

AU - Melton, Douglas A.

N1 - Funding Information: N.S. is partly supported by the Gruss-Lipper Charitable Foundation . D.A.M. is an investigator of the Howard Hughes Medical Institute. This work was supported by grants from the Harvard Stem Cell Institute , Helmsley Charitable Trust and the JPB Foundation . This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (HIRN; RRID: SCR_014393 , UC4 DK104165 , and UC4 DK104159 ). Funding Information: N.S. is partly supported by the Gruss-Lipper Charitable Foundation. D.A.M. is an investigator of the Howard Hughes Medical Institute. This work was supported by grants from the Harvard Stem Cell Institute, Helmsley Charitable Trust and the JPB Foundation. This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (HIRN; RRID:SCR_014393, UC4 DK104165, and UC4 DK104159). We thank Prof. Aviv Regev from the Broad Institute and Dr. Alex Shalek, currently at MIT, for help with technical aspects of scRNAseq; and Mrs. Cathy MacGillvary and Mrs. Diane Faria for histological preparations. Conceptualization, N.S. and D.A.M.; Methodology, N.S. J.S. D.G. and D.A.M.; Software, J.S. J.M. R.C. and C.T.; Validation, N.S. J.V. E.N.E. and Q.Z.; Formal Analysis, N.S. J.S. J.M. Q.Z. and E.N.E.; Investigation, N.S. J.V. Q.Z. and E.N.E.; Resources, C.T. D.K.G. and D.A.M.; Data Curation, J.S. R.C. J.M. and C.T.; Writing ? Original Draft, N.S.; Writing ? Review and Editing, N.S. and D.A.M.; Visualization, N.S. J.V. J.S. and Q.Z.; Funding Acquisition, C.T. D.G. and D.A.M. D.A.M. is a founder and SAB member for Semma Therapeutics. Publisher Copyright: © 2019 The Authors

PY - 2019/5/21

Y1 - 2019/5/21

N2 - In vitro differentiation of pluripotent cells into β cells is a promising alternative to cadaveric-islet transplantation as a cure for type 1 diabetes (T1D). During the directed differentiation of human embryonic stem cells (hESCS) by exogenous factors, numerous genes that affect the differentiation process are turned on and off autonomously. Manipulating these reactions could increase the efficiency of differentiation and provide a more complete control over the final composition of cell populations. To uncover in vitro autonomous responses, we performed single-cell RNA sequencing on hESCs as they differentiate in spherical clusters. We observed that endocrine cells and their progenitors exist beside one another in separate compartments that activate distinct genetic pathways. WNT pathway inhibition in the endocrine domain of the differentiating clusters reveals a necessary role for the WNT inhibitor APC during islet formation in vivo. Accordingly, WNT inhibition in vitro causes an increase in the proportion of differentiated endocrine cells.

AB - In vitro differentiation of pluripotent cells into β cells is a promising alternative to cadaveric-islet transplantation as a cure for type 1 diabetes (T1D). During the directed differentiation of human embryonic stem cells (hESCS) by exogenous factors, numerous genes that affect the differentiation process are turned on and off autonomously. Manipulating these reactions could increase the efficiency of differentiation and provide a more complete control over the final composition of cell populations. To uncover in vitro autonomous responses, we performed single-cell RNA sequencing on hESCs as they differentiate in spherical clusters. We observed that endocrine cells and their progenitors exist beside one another in separate compartments that activate distinct genetic pathways. WNT pathway inhibition in the endocrine domain of the differentiating clusters reveals a necessary role for the WNT inhibitor APC during islet formation in vivo. Accordingly, WNT inhibition in vitro causes an increase in the proportion of differentiated endocrine cells.

KW - APC

KW - Single-cell RNA sequencing

KW - WNT pathway

KW - diabetes

KW - hESCs

KW - human embryonic stem cells

KW - in vitro differentiation

KW - insulin

KW - pancreas development

KW - β cells

UR - https://www.scopus.com/pages/publications/85065771538

U2 - 10.1016/j.celrep.2019.04.083

DO - 10.1016/j.celrep.2019.04.083

M3 - Article

C2 - 31116975

SN - 2211-1247

VL - 27

SP - 2281-2291.e5

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

Wnt Signaling Separates the Progenitor and Endocrine Compartments during Pancreas Development

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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