Exp Mol Med.  2017 Jun;49(6):e350. 10.1038/emm.2017.84.

Lineage conversion of mouse fibroblasts to pancreatic α-cells

Affiliations
  • 1Institute of Biochemistry and Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China. tjliu@sibcb.ac.cn
  • 2Department of Endocrinology and Metabolism, Changzheng Hospital, Second Military Medical University, Shanghai, China. young.stone@163.com
  • 3Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
  • 4Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 5Department of vascular surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
  • 6Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai, China.
  • 7Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto, Canada.

Abstract

α-cells, which synthesize glucagon, also support β-cell survival and have the capacity to transdifferentiate into β-cells. However, the role of α-cells in pathological conditions and their putative clinical applications remain elusive due in large part to the lack of mature α-cells. Here, we present a new technique to generate functional α-like cells. α-like cells (iAlpha cells) were generated from mouse fibroblasts by transduction of transcription factors, including Hhex, Foxa3, Gata4, Pdx1 and Pax4, which induce α-cell-specific gene expression and glucagon secretion in response to KCl and Arg stimulation. The cell functions in vivo and in vitro were evaluated. Lineage-specific and functional-related gene expression was tested by realtime PCR, insulin tolerance test (ITT), glucose tolerance test (GTT), Ki67 and glucagon immunohistochemistry analysis were done in iAlpha cells transplanted nude mice. iAlpha cells possess α-cell function in vitro and alter blood glucose levels in vivo. Transplantation of iAlpha cells into nude mice resulted in insulin resistance and increased β-cell proliferation. Taken together, we present a novel strategy to generate functional α-like cells for the purposes of disease modeling and regenerative medicine.


MeSH Terms

Animals
Blood Glucose
Fibroblasts*
Gene Expression
Glucagon
Glucose Tolerance Test
Immunohistochemistry
In Vitro Techniques
Insulin
Insulin Resistance
Mice*
Mice, Nude
Polymerase Chain Reaction
Regenerative Medicine
Transcription Factors
Blood Glucose
Glucagon
Insulin
Transcription Factors
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