Stage-specific signaling through TGF-beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells

M Cristina Nostro; Farida Sarangi; Shinichiro Ogawa; Audrey Holtzinger; Barbara Corneo; Xueling Li; Suzanne J Micallef; In-Hyun Park; Christina Basford; Michael B Wheeler; George Q Daley; Andrew G Elefanty; Edouard G Stanley; Gordon Keller

doi:10.1242/dev.055236

Stage-specific signaling through TGF-beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells

M Cristina Nostro, Farida Sarangi, Shinichiro Ogawa, Audrey Holtzinger, Barbara Corneo, Xueling Li, Suzanne J Micallef, In-Hyun Park, Christina Basford, Michael B Wheeler, George Q Daley, Andrew G Elefanty, Edouard G Stanley, Gordon Keller

Research output: Contribution to journal › Article › Research › peer-review

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Abstract

The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGFbeta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25 C-peptide+ cells.

Original language	English
Pages (from-to)	861 - 871
Number of pages	11
Journal	Development
Volume	138
Issue number	5
DOIs	https://doi.org/10.1242/dev.055236
Publication status	Published - 2011

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Nostro, M. C., Sarangi, F., Ogawa, S., Holtzinger, A., Corneo, B., Li, X., Micallef, S. J., Park, I-H., Basford, C., Wheeler, M. B., Daley, G. Q., Elefanty, A. G., Stanley, E. G., & Keller, G. (2011). Stage-specific signaling through TGF-beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells. Development, 138(5), 861 - 871. https://doi.org/10.1242/dev.055236

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title = "Stage-specific signaling through TGF-beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells",

abstract = "The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGFbeta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25 C-peptide+ cells.",

author = "Nostro, {M Cristina} and Farida Sarangi and Shinichiro Ogawa and Audrey Holtzinger and Barbara Corneo and Xueling Li and Micallef, {Suzanne J} and In-Hyun Park and Christina Basford and Wheeler, {Michael B} and Daley, {George Q} and Elefanty, {Andrew G} and Stanley, {Edouard G} and Gordon Keller",

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Nostro, MC, Sarangi, F, Ogawa, S, Holtzinger, A, Corneo, B, Li, X, Micallef, SJ, Park, I-H, Basford, C, Wheeler, MB, Daley, GQ, Elefanty, AG, Stanley, EG & Keller, G 2011, 'Stage-specific signaling through TGF-beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells', Development, vol. 138, no. 5, pp. 861 - 871. https://doi.org/10.1242/dev.055236

TY - JOUR

T1 - Stage-specific signaling through TGF-beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells

AU - Nostro, M Cristina

AU - Sarangi, Farida

AU - Ogawa, Shinichiro

AU - Holtzinger, Audrey

AU - Corneo, Barbara

AU - Li, Xueling

AU - Micallef, Suzanne J

AU - Park, In-Hyun

AU - Basford, Christina

AU - Wheeler, Michael B

AU - Daley, George Q

AU - Elefanty, Andrew G

AU - Stanley, Edouard G

AU - Keller, Gordon

PY - 2011

Y1 - 2011

N2 - The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGFbeta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25 C-peptide+ cells.

AB - The generation of insulin-producing beta-cells from human pluripotent stem cells is dependent on efficient endoderm induction and appropriate patterning and specification of this germ layer to a pancreatic fate. In this study, we elucidated the temporal requirements for TGFbeta family members and canonical WNT signaling at these developmental stages and show that the duration of nodal/activin A signaling plays a pivotal role in establishing an appropriate definitive endoderm population for specification to the pancreatic lineage. WNT signaling was found to induce a posterior endoderm fate and at optimal concentrations enhanced the development of pancreatic lineage cells. Inhibition of the BMP signaling pathway at specific stages was essential for the generation of insulin-expressing cells and the extent of BMP inhibition required varied widely among the cell lines tested. Optimal stage-specific manipulation of these pathways resulted in a striking 250-fold increase in the levels of insulin expression and yielded populations containing up to 25 C-peptide+ cells.

UR - http://dev.biologists.org/content/138/5/861.full.pdf+html

U2 - 10.1242/dev.055236

DO - 10.1242/dev.055236

M3 - Article

SN - 0950-1991

VL - 138

SP - 861

EP - 871

JO - Development

JF - Development

IS - 5

ER -

Stage-specific signaling through TGF-beta family members and WNT regulates patterning and pancreatic specification of human pluripotent stem cells

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