Single-cell transcriptomics reveal diverging pathobiology and opportunities for precision targeting in scleroderma -associated versus idiopathic PAH

Pulmonary arterial hypertension (PAH) is characterized by progressive cellular and molecular changes within the pulmonary vasculature that lead to structural remodeling, rising pulmonary vascular resistance and, if untreated, right ventricular failure. In clinical practice, PAH treatments have evolved little over the last two decades, and until recently, all approved therapies have targeted one of three molecular pathways: the nitric oxide (NO) signaling pathway, the endothelin pathway, or the prostacyclin pathway. With these therapies, treatment responses have been modest and variable, with patients experiencing a heterogeneity of treatment effects. In particular, patients with PAH related to systemic sclerosis (SSc-PAH) have derived less benefit from PAH-specific therapies and have experienced worse clinical outcomes compared to other PAH subgroups. We and others have shown that in SSc-PAH, pathophysiologic differences at the molecular, cellular, and tissue levels underlie observed differences in clinical outcomes. A detailed understanding of the molecular aberration present in SSc-PAH versus idiopathic PAH (IPAH) might allow for exploitation of aberrant signaling pathways that are unique to SSc-PAH (and/or present in both of these two common PAH subtypes) for drug targeting. Recently, the approval of sotatercept, a novel ligand-trap molecule that targets TGF-beta signaling in PAH, was based on randomized controlled trial data demonstrating clinical improvement in patients already treated with drugs targeting NO, endothelin, and/or prostacyclin signaling. The success of sotatercept therefore lends credence to the notion that targeting as-yet unaddressed molecular aberrancies can bring about additional clinical benefit. Most previous omics investigations in PAH have examined circulating plasma or serum. With this study, we sought to identify distinct and overlapping gene expression patterns in SSc-PAH versus IPAH human lung tissue as a means of implicating abnormal biological processes, including inferred gene regulation and cell signaling, unique to the organ manifesting disease. To maximize biologic insight, we took a single-cell approach to RNA sequencing, in contrast to the bulk sequencing performed in most previous PAH studies. Finally, we leveraged cell-specific gene expression patterns and established computational methods to identify small molecule compounds with high potential to reverse disease-specific expression signatures, as a means of prioritizing candidates for drug repositioning. We posit that generation of phenotype-specific high-dimensional omics datasets, such as this one, will enable a precision-targeted approach to molecular aberration that might improve therapeutic responses and resolve heterogeneous treatment effects, thereby improving clinical outcomes across PAH subtypes.