Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells

Tyler A. Longmire; Laertis Ikonomou; Finn Hawkins; Constantina Christodoulou; Yuxia Cao; J. C. Jean; Letty W. Kwok; Hongmei Mou; Jayaraj Rajagopal; Steven S. Shen; Anne A. Dowton; Maria Serra; Daniel J. Weiss; Michael D. Green; Hans Willem Snoeck; Maria I. Ramirez; Darrell N. Kotton

doi:10.1016/j.stem.2012.01.019

Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells

Tyler A. Longmire, Laertis Ikonomou, Finn Hawkins, Constantina Christodoulou, Yuxia Cao, J. C. Jean, Letty W. Kwok, Hongmei Mou, Jayaraj Rajagopal, Steven S. Shen, Anne A. Dowton, Maria Serra, Daniel J. Weiss, Michael D. Green, Hans Willem Snoeck, Maria I. Ramirez, Darrell N. Kotton

Institute for Health Informatics

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317 Scopus citations

Abstract

Two populations of Nkx2-1 ⁺ progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using Nkx2-1 ^GFP knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.

Original language	English (US)
Pages (from-to)	398-411
Number of pages	14
Journal	Cell Stem Cell
Volume	10
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2012.01.019
State	Published - Apr 6 2012

Bibliographical note

Funding Information:
We thank Paul Gadue for supplying the TV8-Puro gene targeting vector; Raul Mostoslavsky for assistance with Southern blotting techniques; Susan Guttentag for DCI+K media protocols; and Mary C. Williams, Wellington V. Cardoso, Bess P. Rosen, George Murphy, Gustavo Mostoslavsky, and Jerome Brody for insightful manuscript editing. For technical support, we thank Dr. Yuriy Alekseyev, Sherry Zang, and Dr. Gang Liu for microarray processing; Dr. Jining Lu and Avrum Spira for bioinformatics analysis assistance; and John M. Wallis for lung slice culture technical support. D.N.K. is supported by NIH PO1 HL047049-16A1, 1RC2HL101535-01, 1R01 HL095993-01, 1R01 HL108678, a USAMRRA Award, an Alpha-1 Foundation Award, and an ARC award from the Evans Center for Interdisciplinary Research at Boston University. T.A.L. is supported by NIH training grant T32 HL007035. L.I. is supported by R01 HL111574 and an ATS/ChILD Foundation Award. The authors have no conflicts of interest to declare.

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Longmire, T. A., Ikonomou, L., Hawkins, F., Christodoulou, C., Cao, Y., Jean, J. C., Kwok, L. W., Mou, H., Rajagopal, J., Shen, S. S., Dowton, A. A., Serra, M., Weiss, D. J., Green, M. D., Snoeck, H. W., Ramirez, M. I., & Kotton, D. N. (2012). Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells. Cell Stem Cell, 10(4), 398-411. https://doi.org/10.1016/j.stem.2012.01.019

Longmire, TA, Ikonomou, L, Hawkins, F, Christodoulou, C, Cao, Y, Jean, JC, Kwok, LW, Mou, H, Rajagopal, J, Shen, SS, Dowton, AA, Serra, M, Weiss, DJ, Green, MD, Snoeck, HW, Ramirez, MI & Kotton, DN 2012, 'Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells', Cell Stem Cell, vol. 10, no. 4, pp. 398-411. https://doi.org/10.1016/j.stem.2012.01.019

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title = "Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells",

abstract = "Two populations of Nkx2-1 + progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using Nkx2-1 GFP knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.",

author = "Longmire, {Tyler A.} and Laertis Ikonomou and Finn Hawkins and Constantina Christodoulou and Yuxia Cao and Jean, {J. C.} and Kwok, {Letty W.} and Hongmei Mou and Jayaraj Rajagopal and Shen, {Steven S.} and Dowton, {Anne A.} and Maria Serra and Weiss, {Daniel J.} and Green, {Michael D.} and Snoeck, {Hans Willem} and Ramirez, {Maria I.} and Kotton, {Darrell N.}",

note = "Funding Information: We thank Paul Gadue for supplying the TV8-Puro gene targeting vector; Raul Mostoslavsky for assistance with Southern blotting techniques; Susan Guttentag for DCI+K media protocols; and Mary C. Williams, Wellington V. Cardoso, Bess P. Rosen, George Murphy, Gustavo Mostoslavsky, and Jerome Brody for insightful manuscript editing. For technical support, we thank Dr. Yuriy Alekseyev, Sherry Zang, and Dr. Gang Liu for microarray processing; Dr. Jining Lu and Avrum Spira for bioinformatics analysis assistance; and John M. Wallis for lung slice culture technical support. D.N.K. is supported by NIH PO1 HL047049-16A1, 1RC2HL101535-01, 1R01 HL095993-01, 1R01 HL108678, a USAMRRA Award, an Alpha-1 Foundation Award, and an ARC award from the Evans Center for Interdisciplinary Research at Boston University. T.A.L. is supported by NIH training grant T32 HL007035. L.I. is supported by R01 HL111574 and an ATS/ChILD Foundation Award. The authors have no conflicts of interest to declare. ",

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T1 - Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells

AU - Longmire, Tyler A.

AU - Ikonomou, Laertis

AU - Hawkins, Finn

AU - Christodoulou, Constantina

AU - Cao, Yuxia

AU - Jean, J. C.

AU - Kwok, Letty W.

AU - Mou, Hongmei

AU - Rajagopal, Jayaraj

AU - Shen, Steven S.

AU - Dowton, Anne A.

AU - Serra, Maria

AU - Weiss, Daniel J.

AU - Green, Michael D.

AU - Snoeck, Hans Willem

AU - Ramirez, Maria I.

AU - Kotton, Darrell N.

N1 - Funding Information: We thank Paul Gadue for supplying the TV8-Puro gene targeting vector; Raul Mostoslavsky for assistance with Southern blotting techniques; Susan Guttentag for DCI+K media protocols; and Mary C. Williams, Wellington V. Cardoso, Bess P. Rosen, George Murphy, Gustavo Mostoslavsky, and Jerome Brody for insightful manuscript editing. For technical support, we thank Dr. Yuriy Alekseyev, Sherry Zang, and Dr. Gang Liu for microarray processing; Dr. Jining Lu and Avrum Spira for bioinformatics analysis assistance; and John M. Wallis for lung slice culture technical support. D.N.K. is supported by NIH PO1 HL047049-16A1, 1RC2HL101535-01, 1R01 HL095993-01, 1R01 HL108678, a USAMRRA Award, an Alpha-1 Foundation Award, and an ARC award from the Evans Center for Interdisciplinary Research at Boston University. T.A.L. is supported by NIH training grant T32 HL007035. L.I. is supported by R01 HL111574 and an ATS/ChILD Foundation Award. The authors have no conflicts of interest to declare.

PY - 2012/4/6

Y1 - 2012/4/6

N2 - Two populations of Nkx2-1 + progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using Nkx2-1 GFP knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.

AB - Two populations of Nkx2-1 + progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using Nkx2-1 GFP knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.

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Efficient derivation of purified lung and thyroid progenitors from embryonic stem cells

Abstract

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