INNOVATION OF MESENCHYMAL STEM CELL THERAPIES BY MOLECULAR LANDSCAPING AND CELL SURFACE SELECTION

Mayo Clinic has established an expanding clinical program studying the safety and potential therapeutic use of mesenchymal stem cells (MSC). There is a drive to optimize, improve and expand this new therapy. Intellectual evolution of new clinical strategies for MSCs requires a better understanding of the stem cell types derived from different sources and/or using distinct protocols. This will inform the selection and development of the next generation therapies. Our collaborative research group has developed a novel high-resolution matrix of RNASeq data for several therapeutically relevant MSC types (‘Human MSC Genomics Atlas’). This Atlas defines mRNA levels for 23,338 genes in adipose-tissue derived and bone-marrow derived MSCs, as well as embryonic stem cells. Physiological conditions represented in the dataset include RNASeq data for MSCs exhibiting proliferation, post-proliferative confluence, spontaneous differentiation, tri-lineage differentiation and hypoxia. The molecular behavior of cells was tested on scaffolds using normal growth media or differentiation-inducing conditions. Using bioinformatic and statistical approaches, we define gene expression subsets within the Atlas to identify gene regulatory factors (e.g., transcription factors and epigenetic regulators) that control the biological phenotype and molecular memory of mesenchymal stem cells, as well as the full complement of Cluster of Differentiation markers expressed by these cells. The characterization of new cell surface markers provides experimental avenues for defining distinct subpopulations of MSCs. Also, examination of mRNA expression levels for secreted ligands reveals a ‘virtual protein secretome’ of MSCs that reflect their trophic functions in supporting tissue repair. The Atlas we have generated (and build) provides a roadmap for improving the purity and potency of our current version of MSCs and becomes the foundation to develop improved versions of the next generation of MSC for Mayo.