Regeneration of Thyroid Function by Transplantation of Differentiated Pluripotent Stem Cells

Abstract

Differentiation of functional thyroid epithelia from pluripotent stem cells (PSCs) holds the potential for application in regenerative medicine. However, progress toward this goal is hampered by incomplete understanding of the signaling pathways needed for directed differentiation without forced over-expression of exogenous transgenes. Here we use mouse PSCs to identify key conserved roles for BMP and FGF signaling in regulating thyroid lineage specification from foregut endoderm in mouse and Xenopus. Thyroid progenitors derived from mouse PSCs can be matured into thyroid follicular organoids that provide functional secretion of thyroid hormones in vivo and rescue hypothyroid mice after transplantation. Moreover, by stimulating the same pathways we were also able to derive human thyroid progenitors from normal and disease-specific iPSCs generated from patients with hypothyroidism resulting from NKX2-1 haploinsufficiency. Our studies have therefore uncovered the regulatory mechanisms that underlie early thyroid organogenesis and provide a significant step toward cell-based regenerative therapy for hypothyroidism.

Development of the thyroid gland

“…Postiglione et al, 2002). More recently (Longmire et al, 2012), it was shown that Fgf2 and Bmp4 are necessary and sufficient for the directed differentiation of mouse and human ESCs and human induced pluripotent stem cells (iPSCs) into functional thyrocytes, provided that cells are pre-programmed to definitive endoderm (Kurmann et al, 2015) (Fig. 3B).…”

“…However, although several protocols are now at hand to generate thyroid progenitors and functional follicles from human ESCs or iPSCs (Kurmann et al, 2015;Ma et al, 2015), the field needs further advances (as reviewed by Hollenberg et al, 2016) to make this a realistic possibility. For example, the pool of Nkx2-1 + /Pax8 + thyroid progenitors generated by these approaches is small compared with the number of coinduced lung progenitors, and sorting and enriching precursor cells currently requires genetic labeling (Kurmann et al, 2015). Evidently, additional factors that are of importance for the specification process are still to be identified.…”

“…8A). It is possible that Fgf-and Bmpmediated signals generated in the cardiogenic and pharyngeal mesoderm (Serls et al, 2005;Wendl et al, 2007;Lania et al, 2009;Kurmann et al, 2015) have a role in this process, although a direct mitogenic effect has not been demonstrated. Interestingly, in mice deficient for Hes1, a Notch target and transcriptional repressor, the thyroid bud is smaller and the final thyroid phenotype is hypoplastic, yet the number of BrdU + /Nkx2-1 + cells in the bud is paradoxically increased (Carre et al, 2011).…”

Hypoxia promotes thyroid differentiation of native murine induced pluripotent stem cells

“…Our study also demonstrated that this mechanism may work in the thyroid differentiation. Greater expression of HIF-1a and HIF-2a at all time points together with FGF2 which was a direct transcriptional target of HIFs (Simon et al, 2008) and played an important role in specifying the thyroid lineage (Kurmann et al, 2015) revealed their possible involvement in this promotion by hypoxia. However, because the detail molecular mechanism of thyroid differentiation from murine iPS cells still remains unknown, the topics about whether other mechanisms or factors may get involved in this promotion need our further investigation.…”

“…5A-D). As one of the important downstream genes of HIFs (Simon et al, 2008), fibroblast growth factor 2 (FGF2) is considered to be necessary for thyroid lineage specification from mouse pluripotent stem cells (Kurmann et al, 2015). In order to avoid the interference of exogenous factors, we measured mRNA expression of FGF2 under both conditions with HIFs and the result indicated that hypoxia also significantly increased the level of FGF2 at all the time points (Fig.…”