Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients

Yaxi Zhu, Jason M. Tonne, Qian Liu, Claire A. Schreiber, Zhiguang Zhou, Kuntol Rakshit, Aleksey V Matveyenko, Andre Terzic, Dennis A Wigle, Yogish C Kudva, Yasuhiro Ikeda

Research output: Contribution to journalArticle

Abstract

Generation of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introduced transcription factors, critical for β-cell development and function, in differentiating human induced pluripotent stem cells (PSCs) and assessed the impact on the functionality of derived β-cell (psBC) progeny. A perifusion system revealed stepwise transduction of the PDX1, NEUROG3, and MAFA triad (PNM) enabled in vitro generation of psBCs with glucose and GLP-1 responsiveness within 3 weeks. PNM transduction upregulated genes associated with glucose sensing, insulin secretion, and β-cell maturation. In recipient diabetic mice, PNM-transduced psBCs showed glucose-responsive insulin secretion as early as 1 week post transplantation. Thus, enhanced pre-emptive β-cell specification of PSCs by PNM drives generation of glucose- and incretin-responsive psBCs in vitro, offering a competent tissue-primed biotherapy. In this article, Ikeda Yasuhiro and colleagues show that stepwise transduction of the triad of transcription factors PDX1, NEUROG3, and MAFA (PNM) enabled in vitro generation of glucose- and GLP-1-responsive β cells from iPSCs within 3 weeks. PNM transduction improves glucose sensing, insulin secretion, and β-cell maturation of generated cells. PNM-transduced β cells showed glucose-responsive insulin secretion as early as 1 week post transplantation in diabetic mice.

Original languageEnglish (US)
Pages (from-to)307-321
Number of pages15
JournalStem Cell Reports
Volume13
Issue number2
DOIs
StatePublished - Aug 13 2019

Fingerprint

Glucagon-Like Peptide 1
Transplantation
Glucose
Insulin
Incretins
Stem cells
Transcription Factors
Medical problems
Induced Pluripotent Stem Cells
Pluripotent Stem Cells
Biological Therapy
Genes
Tissue
Specifications

Keywords

  • iPSC
  • MAFA
  • NEUROG3
  • PDX1
  • reprogramming
  • transcription factor
  • β-cell regeneration

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients. / Zhu, Yaxi; Tonne, Jason M.; Liu, Qian; Schreiber, Claire A.; Zhou, Zhiguang; Rakshit, Kuntol; Matveyenko, Aleksey V; Terzic, Andre; Wigle, Dennis A; Kudva, Yogish C; Ikeda, Yasuhiro.

In: Stem Cell Reports, Vol. 13, No. 2, 13.08.2019, p. 307-321.

Research output: Contribution to journalArticle

Zhu, Yaxi ; Tonne, Jason M. ; Liu, Qian ; Schreiber, Claire A. ; Zhou, Zhiguang ; Rakshit, Kuntol ; Matveyenko, Aleksey V ; Terzic, Andre ; Wigle, Dennis A ; Kudva, Yogish C ; Ikeda, Yasuhiro. / Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients. In: Stem Cell Reports. 2019 ; Vol. 13, No. 2. pp. 307-321.
@article{7bfb6b93d2bd4c44b7a1f0419af94998,
title = "Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients",
abstract = "Generation of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introduced transcription factors, critical for β-cell development and function, in differentiating human induced pluripotent stem cells (PSCs) and assessed the impact on the functionality of derived β-cell (psBC) progeny. A perifusion system revealed stepwise transduction of the PDX1, NEUROG3, and MAFA triad (PNM) enabled in vitro generation of psBCs with glucose and GLP-1 responsiveness within 3 weeks. PNM transduction upregulated genes associated with glucose sensing, insulin secretion, and β-cell maturation. In recipient diabetic mice, PNM-transduced psBCs showed glucose-responsive insulin secretion as early as 1 week post transplantation. Thus, enhanced pre-emptive β-cell specification of PSCs by PNM drives generation of glucose- and incretin-responsive psBCs in vitro, offering a competent tissue-primed biotherapy. In this article, Ikeda Yasuhiro and colleagues show that stepwise transduction of the triad of transcription factors PDX1, NEUROG3, and MAFA (PNM) enabled in vitro generation of glucose- and GLP-1-responsive β cells from iPSCs within 3 weeks. PNM transduction improves glucose sensing, insulin secretion, and β-cell maturation of generated cells. PNM-transduced β cells showed glucose-responsive insulin secretion as early as 1 week post transplantation in diabetic mice.",
keywords = "iPSC, MAFA, NEUROG3, PDX1, reprogramming, transcription factor, β-cell regeneration",
author = "Yaxi Zhu and Tonne, {Jason M.} and Qian Liu and Schreiber, {Claire A.} and Zhiguang Zhou and Kuntol Rakshit and Matveyenko, {Aleksey V} and Andre Terzic and Wigle, {Dennis A} and Kudva, {Yogish C} and Yasuhiro Ikeda",
year = "2019",
month = "8",
day = "13",
doi = "10.1016/j.stemcr.2019.07.006",
language = "English (US)",
volume = "13",
pages = "307--321",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

T1 - Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients

AU - Zhu, Yaxi

AU - Tonne, Jason M.

AU - Liu, Qian

AU - Schreiber, Claire A.

AU - Zhou, Zhiguang

AU - Rakshit, Kuntol

AU - Matveyenko, Aleksey V

AU - Terzic, Andre

AU - Wigle, Dennis A

AU - Kudva, Yogish C

AU - Ikeda, Yasuhiro

PY - 2019/8/13

Y1 - 2019/8/13

N2 - Generation of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introduced transcription factors, critical for β-cell development and function, in differentiating human induced pluripotent stem cells (PSCs) and assessed the impact on the functionality of derived β-cell (psBC) progeny. A perifusion system revealed stepwise transduction of the PDX1, NEUROG3, and MAFA triad (PNM) enabled in vitro generation of psBCs with glucose and GLP-1 responsiveness within 3 weeks. PNM transduction upregulated genes associated with glucose sensing, insulin secretion, and β-cell maturation. In recipient diabetic mice, PNM-transduced psBCs showed glucose-responsive insulin secretion as early as 1 week post transplantation. Thus, enhanced pre-emptive β-cell specification of PSCs by PNM drives generation of glucose- and incretin-responsive psBCs in vitro, offering a competent tissue-primed biotherapy. In this article, Ikeda Yasuhiro and colleagues show that stepwise transduction of the triad of transcription factors PDX1, NEUROG3, and MAFA (PNM) enabled in vitro generation of glucose- and GLP-1-responsive β cells from iPSCs within 3 weeks. PNM transduction improves glucose sensing, insulin secretion, and β-cell maturation of generated cells. PNM-transduced β cells showed glucose-responsive insulin secretion as early as 1 week post transplantation in diabetic mice.

AB - Generation of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introduced transcription factors, critical for β-cell development and function, in differentiating human induced pluripotent stem cells (PSCs) and assessed the impact on the functionality of derived β-cell (psBC) progeny. A perifusion system revealed stepwise transduction of the PDX1, NEUROG3, and MAFA triad (PNM) enabled in vitro generation of psBCs with glucose and GLP-1 responsiveness within 3 weeks. PNM transduction upregulated genes associated with glucose sensing, insulin secretion, and β-cell maturation. In recipient diabetic mice, PNM-transduced psBCs showed glucose-responsive insulin secretion as early as 1 week post transplantation. Thus, enhanced pre-emptive β-cell specification of PSCs by PNM drives generation of glucose- and incretin-responsive psBCs in vitro, offering a competent tissue-primed biotherapy. In this article, Ikeda Yasuhiro and colleagues show that stepwise transduction of the triad of transcription factors PDX1, NEUROG3, and MAFA (PNM) enabled in vitro generation of glucose- and GLP-1-responsive β cells from iPSCs within 3 weeks. PNM transduction improves glucose sensing, insulin secretion, and β-cell maturation of generated cells. PNM-transduced β cells showed glucose-responsive insulin secretion as early as 1 week post transplantation in diabetic mice.

KW - iPSC

KW - MAFA

KW - NEUROG3

KW - PDX1

KW - reprogramming

KW - transcription factor

KW - β-cell regeneration

UR - http://www.scopus.com/inward/record.url?scp=85070207252&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070207252&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2019.07.006

DO - 10.1016/j.stemcr.2019.07.006

M3 - Article

VL - 13

SP - 307

EP - 321

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 2

ER -