MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus

Abstract

SUMMARY Mesenchymal stem cell transplantation (MSCT) has been used to treat human diseases, but the detailed mechanisms underlying its success are not fully understood. Here we show that MSCT rescues bone marrow MSC (BMMSC) function and ameliorates osteopenia in Fas-deficient-MRL/lpr mice. Mechanistically, we show that Fas deficiency causes failure of miR-29b release, thereby elevating intracellular miR-29b levels, and downregulates DNA methyltransferase 1 (Dnmt1) expression in MRL/lpr BMMSCs. This results in hypomethylation of the Notch1 promoter and activation of Notch signaling, in turn leading to impaired osteogenic differentiation. Furthermore, we show that exosomes, secreted due to MSCT, transfer Fas to recipient MRL/lpr BMMSCs to reduce intracellular levels of miR-29b, which results in recovery of Dnmt1-mediated Notch1 promoter hypomethylation and thereby improves MRL/lpr BMMSC function. Collectively our findings unravel the means by which MSCT rescues MRL/lpr BMMSC function through reuse of donor exosome-provided Fas to regulate the miR-29b/Dnmt1/Notch epigenetic cascade.

Exosome–Liposome Hybrid Nanoparticles Deliver CRISPR/Cas9 System in MSCs

“…They can transmit a variety of signaling molecules, including nucleic acids mainly mRNA and microRNA, functional proteins, and lipids 12. Owing to the small size of exosomes, they can escape from the rapid phagocytosis by mononuclear phagocytes, steadily carry and deliver drugs in circulation, and pass through vascular endothelium to target cells 13.…”

Long-term safety of umbilical cord mesenchymal stem cells transplantation for systemic lupus erythematosus: a 6-year follow-up study

“…Recently, Liu et al [13] showed that allogeneic MSCT could rescue autologous bone marrow MSCs function and ameliorate osteopenia in Fas-deficient-MRL/lpr mice, which could change the epigenetic cascade in vivo. So the long-term safety of MSCT in human must be emphasized and investigated.…”

Sugar? No Thank You, Just a Deep Breath of Oxygen for Cancer Stem Cells

“…suggested by Liu et al (2015). Potentially, wild-type MSC-EVs could also transfer mRNA, miRNA, cytosolic proteins, and other membrane proteins to elicit and/or potentiate the observed epigenetic changes.…”

“…Meanwhile, although Liu et al (2015) did not investigate if secretory factors other than EVs could supplement Fas function, it is difficult to imagine how cytokines and small molecules can upregulate Fas in cells that lack a functional Fas gene. A complex interplay of signaling factors is typically necessary to elicit epigenetic changes (Mohammad and Baylin, 2010).…”