Minoxidil restores thymic growth in 22q11.2 deletion syndrome by limiting Sox9+ chondrocyte expansion.

Thymic hypoplasia, hypoparathyroidism, and cardiac defects are common congenital malformations caused by 22q11.2 deletion syndrome (22q11.2DS; aka DiGeorge syndrome). Thymus hypoplasia reduces peripheral T cell numbers, leading to more frequent infections. We report that embryonic hypoplastic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) have distinct mesenchymal cell subsets, including an expansion of Sox9+ chondrocytes. Chondrocytes produce collagens and extracellular matrix (ECM) proteins, which can affect thymus size and vascularization. Two compounds, minoxidil and PGE2, restored growth for Tbx1neo2/neo2 embryonic thymuses when administered to pregnant mice prior to formation of the thymic anlage. The dysregulation of the mesenchymal and endothelial transcriptomes was corrected with minoxidil in Tbx1neo2/neo2 thymuses. This was confirmed by the diminished expression of Sox9-driven type II, IX, and XI cartilaginous collagens and other ECM proteins. Furthermore, the location of parathyroids was corrected in Tbx1neo2/neo2 embryos. In summary, these findings reveal that targeting prenatal mesenchymal differentiation can correct multiple congenital anomalies in mouse models of 22q11.2DS.