title: Conversion of mature human β-cells into glucagon-producing α-cells.
abstract: Conversion of one terminally differentiated cell type into another (or transdifferentiation) usually requires the forced expression of key transcription factors. We examined the plasticity of human insulin-producing β-cells in a model of islet cell aggregate formation. Here, we show that primary human β-cells can undergo a conversion into glucagon-producing α-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated β-cell lineage tracing. Converted cells are indistinguishable from native α-cells based on ultrastructural morphology and maintain their α-cell phenotype after transplantation in vivo. Transition of β-cells into α-cells occurs after β-cell degranulation and is characterized by the presence of β-cell-specific transcription factors Pdx1 and Nkx6.1 in glucagon(+) cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the α-cell lineage, inhibits the conversion. Our findings reveal an unknown plasticity of human adult endocrine cells that can be modulated. This endocrine cell plasticity could have implications for islet development, (patho)physiology, and regeneration.
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: H Siebe
authors.initials: HS
authors.lastname: Spijker
authors.forename: Raimond B G
authors.initials: RB
authors.lastname: Ravelli
authors.forename: A Mieke
authors.initials: AM
authors.lastname: Mommaas-Kienhuis
authors.forename: Aart A
authors.initials: AA
authors.lastname: van Apeldoorn
authors.forename: Marten A
authors.initials: MA
authors.lastname: Engelse
authors.forename: Arnaud
authors.initials: A
authors.lastname: Zaldumbide
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.forename: Françoise
authors.initials: F
authors.lastname: Carlotti
authors.forename: Eelco J P
authors.initials: EJ
authors.lastname: de Koning
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000502:physiology*; D050416:Glucagon-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; C105201:NKX6-1 protein, human; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose