Advances and challenges of mesenchymal stem cells for pregnancy-related diseases

Mesenchymal stem cells(MSCs)with pluripotency,wide origin and strong migration ability,but low immunogenicity and lack of ethical controversies,have been intensely investigated for clinical applications within the last decades.Our previously published data in this issue of Cellular and Molecular Immunology demonstrated that adoptive transfer of MSCs can prevent fetal loss in lipopolysaccharide-induced and spontaneous abortion models via a paracrine effect and a cell contact-dependent manner.

SMYD3-PARP16 axis accelerates unfolded protein response and mediates neointima formation

Neointimal hyperplasia after vascular injury is a representative complication of restenosis.Endoplasmic reticulum(ER)stress-induced unfolded protein response(UPR)is involved in the pathogenesis of vascular intimal hyperplasia.PARP16,a member of the poly(ADP-ribose)polymerases family,is correlated with the nuclear envelope and the ER.Here,we found that PERK and IRE1 a are ADPribosylated by PARP16,and this might promote proliferation and migration of smooth muscle cells(SMCs)during the platelet-derived growth factor(PDGF)-BB stimulating.Using chromatin immunoprecipitation coupled with deep sequencing(ChIP-seq)analysis,PARP16 was identified as a novel target gene for histone H3 lysine 4(H3 K4)methyltransferase SMYD3,and SMYD3 could bind to the promoter of Parp16 and increased H3 K4 me3 level to activate its host gene’s transcription,which causes UPR activation and SMC proliferation.Moreover,knockdown either of PARP16 or SMYD3 impeded the ER stress and SMC proliferation.On the contrary,overexpression of PARP16 induced ER stress and SMC proliferation and migration.In vivo depletion of PARP16 attenuated injury-induced neointimal hyperplasia by mediating UPR activation and neointimal SMC proliferation.This study identified SMYD3-PARP16 is a novel signal axis in regulating UPR and neointimal hyperplasia,and targeting this axis has implications in preventing neointimal hyperplasia related diseases.

Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis

Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of inflammation.Jumonji domain-containing protein 3(JMJD3)is implicated in the immune response and inflammation.Here,we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis(RA).Upregulated CSE and JMJD3 were identified in synovial fibroblasts(SFs)from RA patients as well as in the joints of arthritic mice.Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression.In addition,CSE−/−mice with collagen-induced arthritis(CIA)developed severe joint inflammation and bone erosion.Conversely,overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs.Furthermore,JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs,mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes.GSK-J4 markedly attenuated the severity of arthritis in CIA mice.In conclusion,suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.