Abstract
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.
Highlights
Accidental cell fusion might enable catastrophic events including the development of tumor cells and/ or metastatic spread of tumor cells
We take the case of fusion of multipotent stem/stromal cells (MSCs) with cardiomyocytes, which has been detected by mulitiple investigators in vivo[1,4,5,6,7,8,9]
Single-cell transcriptome analysis of hybrids by RNA-seq should enable direct comparison of individual fusion products with parental cells to determine the degree of programming/reprogramming in hybrid cells toward one or both of the parental cells, the rapidity with which programming/reprogramming occurs and the extent to which unique advantageous or deleterious transcriptome features emerge
Summary
Accidental cell fusion might enable catastrophic events including the development of tumor cells and/ or metastatic spread of tumor cells. Spontaneous fusion has been reported between normal breast epithelium and breast cancer cells[37,38], among breast tumor cells themselves[39,40], and between breast cancer epithelium and tumor stromal cells including MSCs41,42. We probe the extent of transcriptional diversification of hybrids formed between MSCs and cardiomyocytes, and the beneficial or detrimental outcomes of diversification at the single cell level. We probe this particular cell pairing as hybrids of this type have been most frequently reported in the context of cell transplantation to the heart. We utilize single-cell RNA-seq since each hybrid is predicted to be transcriptionally distinct and population analyses may mute unique expression profiles
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