Human organoids to study the molecular networks controlling differentiation of progenitor cells toward thyroid or lung cell epithelium

In the anterior foregut endoderm, Nkx2.1 + progenitor cells give rise to thyroid follicle cells that produce thyroid hormones, that regulate body metabolism, growth, and development. Lack of thyroid hormone early in development, termed congenital hypothyroidism, can lead to severe malformations, including mental retardation, goiter or dwarfism.

Interestingly, Nkx2.1 + progenitor cells give also rise cells of the lung/airway epithelium (epithelium (Mucus cells, Ciliated cells, basal cells, Clara cells, type 1 and 2 alveolar cells…). The failure of the lung epithelium to regenerate and repair itself, that occurs with ageing or in patients with chronic obstructive pulmonary disease (COPD) , could be a consequence of depletion of the endogenous pool of lung progenitor cells or their limited ability to differentiate.

The molecular networks that control the cell fate decision of these Nkx2.1 + progenitor cells toward thyroid or lung epithelium are still largely unknown.

In recent years, significant progress has been made in the development and application of human cell-based models for the study of human biology and disease modeling. Protocols based on human embryonic stem cells (ESC) have been developed and have resulted in the generation of several types of human organoids, including brain, intestine, stomach, liver, kidney, lung, endometrium, prostate, pancreas, and retina

Our laboratory has developed a protocol to generate hormone-producing human thyroid organoids¹ from hESCs in vitro that are capable of restoring thyroid hormone production after transplantation into immunodeficient hypothyroid mice². Interestingly, addition of only one hormone in the culture conditions used to generate human thyroid organoids suppressed thyroid differentiation and instead generated mature and functional lung organoids.

Using state-of-the-art techniques (scRNAseq, ATAQseq, CRISPR editing), the goal of this project is to 1) document the dynamics of gene expression underlying human thyroid and lung development in our experimental model, 2) unravel the molecular network controlling cell lineage decisions of Nkx2.1 + progenitor cells 3) Identify pathways that could increase the pool of lung progenitor cells involved in lung regeneration/repair or stimulate the endogenous regenerative ability of lung cells.

1. Antonica, F. et al. Generation of functional thyroid from embryonic stem cells. Nature 491, 66–71 (2012).
2. Romitti, M. et al. Transplantable human thyroid organoids generated from embryonic stem cells to rescue hypothyroidism. Nat Commun 13, 7057 (2022). https://doi.org/10.1038/s41467-022-34776-7, https://doi.org/10.1038/s41467-022-34776-7