Proteomics identifies multipotent and low oncogenic risk stem cells of the spleen

The adult spleen harbors a population of naturally occurring multipotent stem cells of non-lymphoid lineage (CD45−). In animal models, these splenic stem cells can directly or indirectly contribute to regeneration of bone, inner ear, cranial nerves, islets, hearts and salivary glands. Here we characterize the CD45− stem cell proteome to determine its potential broader multipotency versus its protection from malignant transformation. Using state-of-the-art proteomics and in vivo testing, we performed functional analyses of unique proteins of CD45− (non-lymphoid) splenic stem cells, as compared with CD45+ (lymphoid) cells. CD45− stem cell-specific proteins were identical to those in iPS, including OCT3/4, SOX2, KLF4, c-MYC and NANOG. They also expressed Hox11, Gli3, Wnt2, and Adam12, the benchmark transcription factors of embryonic stem cells. These transcription factors were functional because their mRNA was upregulated in the spleen in association with ongoing damage to the pancreas and salivary glands, organs to which they normally contribute stem cells. We also show low likelihood of malignant transformation. Our proteomic and functional analyses reveals that naturally occurring CD45− stem cells of the spleen are the first-ever candidates for naturally occurring population of embryonic and iPS cells with low oncogenic risk. Given their presence in normal humans and mice, splenic stem cells are poised for translational research.