Mesenchymal stem cells from bone marrow, fat, and other tissues have been used in many clinical trials, experiments, and treatment regimens. While these cells are not magic bullets, they do have the ability to suppress unwanted inflammation, differentiate into bone, cartilage, tendon, smooth muscle, and fat, and can release a variety of healing molecules that help organs from hearts to kidneys heal themselves.
Mesenchymal stem cell transplantation (MSCT) is the main means by which mesenchymal stem cells are delivered to patients for therapeutic purposes. However, the precise mechanisms that underlie the success of these cells are not fully understood. In a paper by from the University Of Pennsylvania School Of Dental Medicine published in the journal Cell Metabolism, MSCT were able to re-establish the bone marrow function in MRL/lpr mice. The MRL/lpr mouse is a genetic model of a generalized autoimmune disease sharing many features and organ pathology with systemic lupus erythematosus (SLE). Such mice show bone loss and poor bone deposition, a condition known as “osteopenia.” Because mesenchymal stem cells are usually the cells in bone marrow that differentiate into osteoblasts (which make bone) a condition like osteopenia results from defective mesenchymal stem cell function.
In this paper, Shi and his coworkers and collaborators showed that the lack of the Fas protein in the mesenchymal stem cells from MRL/lpr mice prevents them from releasing a regulatory molecule called “miR-29b.” This regulatory molecule, mir-29b, is a small RNA molecule known as a microRNA. MicroRNAs regulate the expression of other genes, and the failure to release miR-29b increases the intracellular levels of miR-29b. This build-up in the levels of miR-29b causes the downregulation of an enzyme called “DNA methyltransferase 1” or Dnmt1. This is not surprising, since this is precisely what microRNAs do – they regulate genes. Dnmt1 attaches methyl groups (CH3 molecules) to the promoter or control regions of genes.
Decrease in the levels of Dnmt1 causes hypomethylation of the Notch1 promoter. When promoters are heavily methylated, genes are poorly expressed. When very methyl groups are attached to the promoters, then the gene has a greater chance of being highly expressed. Robust expression of the Notch1 genes activates Notch signaling. Increased Notch signaling leads to impaired bone production, since differentiation into bone-making cells requires mesenchymal stem cells to down-regulate Notch signaling.
When normal mesenchymal stem cells are transplanted into the bone marrow of MRL/lpr mice, they release small vesicles called exosomes that transfer the Fas protein to recipient MRL/lpr bone marrow mesenchymal stem cells. The presence of the Fas protein reduces intracellular levels of miR-29b, and this increases Dnmt1-mediated methylation of the Notch1 promoter. This decreases the expression of Notch1 and improves MRL/lpr BMMSC function.
These findings elucidate the means by which MSCT rescues MRL/lpr BMMSC function. Since MRL/lpr mice are a model system for lupus, it suggests that donor mesenchymal stem cell transplantation into lupus patients provides Fas protein to the defective, native mesenchymal stem cells, thereby regulating the miR-29b/Dnmt1/Notch epigenetic cascade that increases differentiation of mesenchymal stem cells into osteoblasts and bone deposition rates.