Generation of Thyroid Tissues From Embryonic Stem Cells via Blastocyst Complementation In Vivo

Abstract

The generation of mature, functional, thyroid follicular cells from pluripotent stem cells would potentially provide a therapeutic benefit for patients with hypothyroidism, but in vitro differentiation remains difficult. We earlier reported the in vivo generation of lung organs via blastocyst complementation in fibroblast growth factor 10 (Fgf10), compound, heterozygous mutant (Fgf10 Ex1mut/Ex3mut) mice. Fgf10 also plays an essential role in thyroid development and branching morphogenesis, but any role thereof in thyroid organogenesis remains unclear. Here, we report that the thyroids of Fgf10 Ex1mut/Ex3mut mice exhibit severe hypoplasia, and we generate thyroid tissues from mouse embryonic stem cells (ESCs) in Fgf10 Ex1mut/Ex3mut mice via blastocyst complementation. The tissues were morphologically normal and physiologically functional. The thyroid follicular cells of Fgf10 Ex1mut/Ex3mut chimeric mice were derived largely from GFP-positive mouse ESCs although the recipient cells were mixed. Thyroid generation in vivo via blastocyst complementation will aid functional thyroid regeneration.

Derivation of Thyroid Follicular Cells From Pluripotent Stem Cells: Insights From Development and Implications for Regenerative Medicine

“…Recently, Wen et al used intra-species blastocyst complementation to produce ESC-derived lungs and thyroids in Nkx2-1 -/mouse embryos lacking these tissues; interestingly, histological analysis of these embryos at E17.5 confirmed the efficient restoration of thyrocyte progenitor cells, expressing both NKX2-1/PAX8 (81). In a similar vein, Ran et al showed high thyroid contribution of donor ESCs and restoration of thyroid gland size and function in Fgf10 Ex1 mut /Ex3 mut mice that lack Fgf10 expression (82).…”

In Vivo Generation of Organs by Blastocyst Complementation: Advances and Challenges

“…This study demonstrated the limitations in using mutated genes expressing secreted factors in blastocyst complementation studies ( 28 ). Fgf10 mutant blastocysts were also used in another study to generate allogeneic thyroids that were largely, but not exclusively, derived from donor cells ( 29 ). An even more recent study used Nkx2-1 mutant embryos, which lack pulmonary and thyroid tissues.…”

Stem Cell Therapy for Thyroid Diseases: Progress and Challenges

“… 56 Exosomes are promising in the cell-free therapeutic strategy for future studies. Recently, Wen et al 57 , 58 reported that mouse ESC complementation induces thyroid morphogenesis in Nkx2-1 −/− embryos (Nkx2-1 gene knockout embryos mice) and Fgf10 Ex1mut/Ex3mut mice (Fgf10 Ex1 genes mutation mice/Ex3 gene mutation mice). These generated tissues have normal morphology and physiological function.…”