R-SPONDIN2+ mesenchymal cells form the bud tip progenitor niche during human lung development

The human respiratory epithelium is derived from a progenitor cell in the distal buds of the developing lung. These bud tip progenitors'' are regulated by reciprocal signaling with surrounding mesenchyme; however, mesenchymal heterogeneity and function in the developing human lung are poorly understood. We interrogated single-cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of theWNT agonist RSPO2, and we found that the adjacent bud tip progenitors are enriched for the RSPO2 receptor LGR5. Functional experiments using organoid models, explant cultures, and FACS-isolated RSPO2(+) mesenchyme show that RSPO2 is a critical niche cue that potentiates WNT signaling in bud tip progenitors to support their maintenance and multipotency.

Automated summary

During human lung development, there is a population of mesenchymal cells highly enriched for the RSPO2 gene expression, which plays a critical role in supporting the maintenance and multipotency of the nearby bud tip progenitor cells through enhancing WNT signaling.