Conversion of mature human beta-cells into glucagon-producing alpha-cells

TY - JOUR

T1 - Conversion of mature human beta-cells into glucagon-producing alpha-cells

AU - Spijker, H.S.

AU - Ravelli, R.B.

AU - Mommaas-Kienhuis, A.M.

AU - van Apeldoorn, A.A.

AU - Engelse, M.A.

AU - Zaldumbide, A.

AU - Bonner-Weir, S.

AU - Rabelink, T.J.

AU - Hoeben, R.C.

AU - Clevers, H.

AU - Mummery, C.L.

AU - Carlotti, F.

AU - de Koning, E.

N1 - Reporting year: 2013

PY - 2013

Y1 - 2013

N2 - 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 beta-cells in a model of islet cell aggregate formation. Here, we show that primary human beta-cells can undergo a conversion into glucagon-producing alpha-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated beta-cell lineage tracing. Converted cells are indistinguishable from native alpha-cells based on ultrastructural morphology and maintain their alpha-cell phenotype after transplantation in vivo. Transition of beta-cells into alpha-cells occurs after beta-cell degranulation and is characterized by the presence of beta-cell-specific transcription factors Pdx1 and Nkx6.1 in glucagon(+) cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the alpha-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.

AB - 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 beta-cells in a model of islet cell aggregate formation. Here, we show that primary human beta-cells can undergo a conversion into glucagon-producing alpha-cells without introduction of any genetic modification. The process occurs within days as revealed by lentivirus-mediated beta-cell lineage tracing. Converted cells are indistinguishable from native alpha-cells based on ultrastructural morphology and maintain their alpha-cell phenotype after transplantation in vivo. Transition of beta-cells into alpha-cells occurs after beta-cell degranulation and is characterized by the presence of beta-cell-specific transcription factors Pdx1 and Nkx6.1 in glucagon(+) cells. Finally, we show that lentivirus-mediated knockdown of Arx, a determinant of the alpha-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.

U2 - 10.2337/db12-1001

DO - 10.2337/db12-1001

M3 - Article

VL - 62

SP - 2471

EP - 2480

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 7

ER -