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Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients
- Source :
- Stem Cell Reports, Stem Cell Reports, Vol 13, Iss 2, Pp 307-321 (2019)
- Publication Year :
- 2018
-
Abstract
- 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.<br />Highlights • PNM transduction facilitates generation of glucose- and GLP1-responsive β cells • Stepwise PNM improves glucose sensing, insulin secretion, and β-cell maturation • PNM-transduced psBCs showed glucose-responsive insulin secretion in diabetic mice<br />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.
- Subjects :
- 0301 basic medicine
Maf Transcription Factors, Large
Mice, SCID
Biochemistry
Transduction (genetics)
Mice
0302 clinical medicine
Glucagon-Like Peptide 1
Transduction, Genetic
NEUROG3
Insulin-Secreting Cells
Insulin Secretion
Basic Helix-Loop-Helix Transcription Factors
lcsh:QH301-705.5
transcription factor
lcsh:R5-920
PDX1
iPSC
C-Peptide
Cell Differentiation
MAFA
3. Good health
Cell biology
Homeobox Protein Nkx-2.2
β-cell regeneration
lcsh:Medicine (General)
Reprogramming
endocrine system
Induced Pluripotent Stem Cells
Incretin
Nerve Tissue Proteins
Biology
Article
Diabetes Mellitus, Experimental
03 medical and health sciences
Downregulation and upregulation
Diabetes mellitus
Genetics
medicine
Animals
Humans
Transcription factor
Homeodomain Proteins
reprogramming
Cell Biology
Glucose Tolerance Test
Zebrafish Proteins
medicine.disease
Transplantation
030104 developmental biology
Glucose
lcsh:Biology (General)
Gene Expression Regulation
Trans-Activators
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- ISSN :
- 22136711
- Volume :
- 13
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Stem cell reports
- Accession number :
- edsair.doi.dedup.....e03d871ef290d1daa4bc71f6691ef08c