Single-cell RNA-seq reveals activation of unique gene groups as a consequence of stem cell-parenchymal cell fusion
Fusion of donor mesenchymal stem cells with parenchymal cells of the recipient can occur in the brain, liver, intestine and heart following transplantation. The therapeutic benefit or detriment of resultant hybrids is unknown. Here we sought a global view of phenotypic diversification of mesenchymal stem cell-cardiomyocyte hybrids and associated time course. Using single-cell RNA-seq, we found hybrids consistently increase ribosome components and decrease genes associated with the cell cycle suggesting an increase in protein production and decrease in proliferation to accommodate the fused state. But in the case of most other gene groups, hybrids were individually distinct. In fact, though hybrids can express a transcriptome similar to individual fusion partners, approximately one-third acquired distinct expression profiles in a single day. Some hybrids underwent reprogramming, expressing pluripotency and cardiac precursor genes latent in parental cells and associated with developmental and morphogenic gene groups. Other hybrids expressed genes associated with ontologic cancer sets and two hybrids of separate experimental replicates clustered with breast cancer cells, expressing critical oncogenes and lacking tumor suppressor genes. Rapid transcriptional diversification of this type garners consideration in the context of cellular transplantation to damaged tissues, those with viral infection or other microenvironmental conditions that might promote fusion. Overall design: Examination was performed using single-cell RNA-seq of five fusion products (BiFC_D1_F1-5, 24 hours) identified using BiFC, twenty-three fusion products (DC_D1_F1-16, 24 hours; DC_D3_F1-7, 72 hours) identified using dual expression of GFP and mCherry, the parental controls, and the population controls (mMSC_PC and HL1cm_PC). Parental controls included 15 cells of each parental type isolated prior to co-culture (mMSC_1-15 and HL1cm_1-15) and 5 cells of each parental cell type isolated 24 hours after co-culture (mMSC_D1_1-5 and HL1cm_D1_1-5). In addition, a population containing a mixture of both parental cells and fusion products obtained 24 hours after co-culture was included (Mix_D1).
External Link: /pubmed:26997336