Single-cell RNA sequencing identifies KSHV-infected Mesenchymal stem cell subpopulations precursors of Kaposi’s Sarcoma

ABSTRACT Kaposi’s sarcoma (KS) may derive from Kaposi’s Sarcoma Herpesvirus (KSHV)-infected human Mesenchymal Stem Cells (hMSCs) migrating into an inflammatory and angiogenic site, enhancing KS initiation. KSHV infection of primary hMSCs uncovers specific cell subpopulations, mechanisms, and conditions involved in the first steps of the KSHV-induced transformation and reprogramming process toward KS progenitor cells. The pro-angiogenic environmental conditions allowed KSHV to reprogram hMSCs closer to KS gene expression profiles and points to KSHV infection as an important factor inducing the Mesenchymal-to-Endothelial (MEndT) transition of hMSC. Single-cell RNA-sequencing analysis revealed a subpopulation of infected cells growing in a pro-angiogenic environment with both viral and host oncogenes upregulation. This highlights the importance of this condition in boosting the KSHV-induced transformation and reprogramming of hMSC towards MEndT and closer to KS gene expression profiles, reinforcing the notion of these cell subpopulations as KS precursors.