Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients
Summary: 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....
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2019-08-01
|
Series: | Stem Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671119302589 |
id |
doaj-5560a206141740e1b439ccf39e142bc3 |
---|---|
record_format |
Article |
spelling |
doaj-5560a206141740e1b439ccf39e142bc32020-11-25T02:39:50ZengElsevierStem Cell Reports2213-67112019-08-01132307321Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic RecipientsYaxi Zhu0Jason M. Tonne1Qian Liu2Claire A. Schreiber3Zhiguang Zhou4Kuntol Rakshit5Aleksey V. Matveyenko6Andre Terzic7Dennis Wigle8Yogish C. Kudva9Yasuhiro Ikeda10Department of Molecular Medicine, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, ChinaDepartment of Molecular Medicine, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN 55905, USADepartment of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Molecular Medicine, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN 55905, USAInstitute of Metabolism and Endocrinology, The Second Xiangya Hospital, Key Laboratory of Diabetes Immunology, Ministry of Education, Central South University, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, ChinaDepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USADepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA; Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USACenter for Regenerative Medicine, Mayo Clinic, Rochester, MN, USACenter for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA; Division of Thoracic Surgery, Mayo Clinic, Rochester, MN, USADivision of Endocrinology, Mayo Clinic, Rochester, MN, USADepartment of Molecular Medicine, Mayo Clinic, College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA; Corresponding authorSummary: 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, reprogramming, β-cell regeneration, transcription factor, PDX1, NEUROG3, MAFAhttp://www.sciencedirect.com/science/article/pii/S2213671119302589 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yaxi Zhu Jason M. Tonne Qian Liu Claire A. Schreiber Zhiguang Zhou Kuntol Rakshit Aleksey V. Matveyenko Andre Terzic Dennis Wigle Yogish C. Kudva Yasuhiro Ikeda |
spellingShingle |
Yaxi Zhu Jason M. Tonne Qian Liu Claire A. Schreiber Zhiguang Zhou Kuntol Rakshit Aleksey V. Matveyenko Andre Terzic Dennis Wigle Yogish C. Kudva Yasuhiro Ikeda Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients Stem Cell Reports |
author_facet |
Yaxi Zhu Jason M. Tonne Qian Liu Claire A. Schreiber Zhiguang Zhou Kuntol Rakshit Aleksey V. Matveyenko Andre Terzic Dennis Wigle Yogish C. Kudva Yasuhiro Ikeda |
author_sort |
Yaxi Zhu |
title |
Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients |
title_short |
Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients |
title_full |
Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients |
title_fullStr |
Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients |
title_full_unstemmed |
Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients |
title_sort |
targeted derivation of organotypic glucose- and glp-1-responsive β cells prior to transplantation into diabetic recipients |
publisher |
Elsevier |
series |
Stem Cell Reports |
issn |
2213-6711 |
publishDate |
2019-08-01 |
description |
Summary: 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, reprogramming, β-cell regeneration, transcription factor, PDX1, NEUROG3, MAFA |
url |
http://www.sciencedirect.com/science/article/pii/S2213671119302589 |
work_keys_str_mv |
AT yaxizhu targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT jasonmtonne targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT qianliu targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT claireaschreiber targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT zhiguangzhou targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT kuntolrakshit targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT alekseyvmatveyenko targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT andreterzic targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT denniswigle targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT yogishckudva targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients AT yasuhiroikeda targetedderivationoforganotypicglucoseandglp1responsivebcellspriortotransplantationintodiabeticrecipients |
_version_ |
1724784487739424768 |