Editors' ChoiceStem Cell Biology

Leaving a lasting impression

Sci. Signal.  13 Oct 2015:
Vol. 8, Issue 398, pp. ec290
DOI: 10.1126/scisignal.aad6062

Individuals with systemic lupus erythematosus (SLE) are at increased risk for reduced bone mass, severe forms of which are called osteoporosis. One treatment for SLE is mesenchymal stem cell (MSC) transplantation, although the beneficial effects usually outlast the transplanted MSCs (see the commentary by Ng et al.). Liu et al. found that when implanted in MRL/lpr mice, which have a mutation in the death receptor Fas and are a model for SLE, transplanted bone marrow MSCs (BMMSCs) from wild-type mice released exosomes that were taken up by MRL/lpr BMMSCs. In vitro, the Fas in these exosomes was integrated into MRL/lpr BMMSCs, which increased the release of the microRNA miR-29b, thereby reducing its intracellular abundance and increasing the abundance of the DNA demethylase Dnmt1 (a target of miR-29b) as well as the methylation of the Notch1 promoter (a target of Dnmt1). Notch signaling promotes the maintenance of an undifferentiated state in stem cells, and MRL/lpr BMMSCs showed hypomethylation of the Notch1 promoter, increased expression of various Notch target genes, and decreased ability to form bone in vivo when implanted into immunocompromised mice with hydroxyapatite tricalcium phosphate as a carrier. Transplantation of BMMSCs from wild-type mice improved the bone mineral density and thus lessened the osteoporotic phenotype of MRL/lpr mice, and also increased the ability of BMMSCs from MRL/lpr mice to form bone in vivo. These effects were mimicked to varying degrees when MRL/lpr mice were treated with exosomes from wild-type BMMSCs, a miR-29b inhibitor, the Notch signaling inhibitor DAPT, or a Notch-specific siRNA. Thus, these results suggest that exosomes from transplanted MSCs stimulate the epigenetic reprogramming of recipient MSCs to rescue their function.

S. Liu, D. Liu, C. Chen, K. Hamamura, A. Moshaverinia, R. Yang, Y. Liu, Y. Jin, S. Shi, MSC transplantation improves osteopenia via epigenetic regulation of Notch signaling in lupus. Cell Metab. 22, 606–618 (2015). [PubMed]

K. S. Ng, T. M. Kuncewicz, J. M. Karp, Beyond hit-and-run: Stem cells leave a lasting memory. Cell Metab. 22, 541–543 (2015). [PubMed]