Sabine Costagliola Lab

Pluripotent Stem cells to model thyroid development and associated diseases.


Our lab has recently demonstrated the generation of functional thyroid tissue in a three-dimensional mouse embryonic stem cell (mESC) culture system (Antonica et al. Nature 2012). In this work, we first report how doxycycline induction of two transcription factors, NKX2.1 and PAX8, directs mESC differentiation towards a thyroid follicular cell (TFC) fate.


Then, we demonstrate that subsequent treatment with recombinant human TSH promotes efficient self-assembly of TFC-like cells into three-dimensional organoids displaying molecular, morphological and functional properties of bona fide thyroid follicles. Finally, we clearly demonstrate that mESC-derived TFC, when grafted under the kidney capsules of female hypothyroid mice, develop into functional thyroid tissue capable of rescuing thyroid hormone deficits (hypothyroidism).


Patient-specific IPS cells represent a powerful tool to investigate cellular and molecular mechanisms leading to disease. Our project aims at recapitulating normal and pathological human thyroid gland development in vitro, from IPS cells derived from patients with sporadic congenital hypothyroidism or from cells that carry mutations known to increase thyroid cancer risk.


 

Zebrafish to study molecular and cellular mechanisms regulating the coordinated development of thyroid and cardiovascular system.




Development is a complex process involving various morphogenetic events such as precursor cell specification in ventral foregut endoderm, thyroid budding, migration of the primordium to a position distant from its site of origin and formation of functional thyroid follicles.

Based on our knowledge about organogenesis of other foregut derivatives, one can predict a complex interplay of extrinsic and intrinsic factors to regulate these morphogenetic events. Importantly, the coordinated development of the thyroid along specific cardiovascular structures suggests a critical role of the cardiovascular system as a source of morphogenic signals and as a scaffold to guide thyroid morphogenesis.

Research on thyroid morphogenesis was missing one vital tool: a transgenic model that allows visualizing the complex morphogenetic processes occurring in living embryos. We have recently developed novel transgenic zebrafish lines in which a robust thyroid-specific fluorescent reporter signal is activated shortly after thyroid precursor cell specification. This model system provides an unprecedented opportunity to visualize thyroid organogenesis and to study thyroid function in live embryos and to define cellular and molecular mechanisms involved in those processes.

 

see following publications:


Opitz R*, Maquet E*, Huisken J, Antonica F, Trubiroha A, Pottier G, Janssens V, Costagliola S. 

Transgenic zebrafish illuminate the dynamics of thyroid morphogenesis and its relationship to cardiovascular development. Dev Biol 2012: 372 (2), 203–216.


Opitz R*, Maquet E*, Zoenen M, Dadhich R, Costagliola S.

TSH receptor function is required for normal thyroid differentiation in zebrafish. Mol Endocrinol. 2011 Sep;25(9):1579-99.


Opitz.R*, M.-P. Hitz*, I. Vandernoot, A. Trubiroha, R. Abu-Khudir, M. Samuels, V. Désilets, S.Costagliola*, G. Andelfinger*, and J. Deladoëy*.

Functional zebrafish studies based on human genotyping point to netrin-1 as a link between aberrant cardiovascular development and thyroid dysgenesis.

Endocrinology. 2015: vol. 156, no. 1, pp. 377–388.


*: contributed equally.

see following publications:


Antonica F, Figini-Kasprzyk D, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, Peremans K, Manto M, Kyba M, Costagliola S.

Generation of functional thyroid from embryonic stem cells.

Nature. 2012 (491): 66-71



Thyroid is latest success in regenerative medicine.

Dan Jones

Nature 2012 Oct.10. doi:10.1038/nature.2012.11574

 

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