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Rationale  The lung mesenchyme gives rise to multiple distinct lineages of cells in the mature respiratory system, including smooth muscle cells of the airway and vasculature. However, a thorough understanding of the specification and mesenchymal cell diversity in the human lung is lacking.    Methods  We completed single-cell RNA sequencing analysis of fetal human lung tissues. Canonical correlation analysis, clustering, cluster marker gene identification and t-distributed stochastic neighbour embedding representation was performed in Seurat. Cell populations were annotated using ToppFun. Immunohistochemistry and  in situ  hybridisation were used to validate spatiotemporal gene expression patterns for key marker genes.    Results  We identified molecularly distinct populations representing “committed” fetal human lung endothelial cells, pericytes and smooth muscle cells. Early endothelial lineages expressed “classic” endothelial cell markers (platelet endothelial cell adhesion molecule/CD31 and claudin 5), while pericytes expressed platelet-derived growth factor receptor-β, Thy-1 membrane glycoprotein and basement membrane molecules (collagen IV, laminin and proteoglycans). We observed a large population of “nonspecific” human lung mesenchymal progenitor cells characterised by expression of collagen I and multiple elastin fibre genes ( ELN ,  MFAP2  and  FBN1 ). We closely characterised the diversity of mesenchymal lineages defined by α 2 -smooth muscle actin ( ACTA2 ) expression. Two cell populations, with the highest levels of  ACTA2  transcriptional activity, expressed unique sets of markers associated with airway or vascular smooth muscle cells. Spatiotemporal analysis of these marker genes confirmed early and persistent spatial specification of airway ( HHIP ,  MYLK  and  IGF1 ) and vascular ( NTRK3  and  MEF2C ) smooth muscle cells in the developing human lung.    Conclusion  Our data suggest that specification of distinct airway and vascular smooth muscle cell phenotypes is established early in development and can be identified using the markers we provide.

Transcriptional characterisation of human lung cells identifies novel mesenchymal lineage markers