The effect of lncRNA MIR155HG-modified MSCs and exosome delivery to synergistically attenuate vein graft intimal hyperplasia

Abstract

Background The mesenchymal stem cells (MSCs) were used to repair tissue injury. However, the treatment effect was not satisfactory. We investigated whether lncRNA MIR155HG could promote survival and migration of MSCs under oxidative stress, which mimics in vivo environments. Furthermore, we studied the protective effect of exosomes secreted by MSCs transfected with MIR155HG on endothelial cells. This study aimed to determine whether exploiting MSCs and exosomes modified with lncRNA MIR155HG would exert synergistic therapeutic effect to attenuate vein graft intimal hyperplasia more effectively. Methods Lentivirus containing lncRNA MIR155HG overexpressing vector was packaged and used to infect MSCs. Then, CCK-8 assay, flow cytometry, Transwell assay, and Elisa assay were used to assess the functional changes of MSCs with overexpressed MIR155HG (OE-MSCs). Furthermore, the associated pathways were screened by Western blot. MIR155HG-MSCs-derived exosomes (OE-exo) were collected and co-cultured with human umbilicus vein endothelial cell (HUVEC). We validated the protective effect of OE-exo on HUVEC. In vivo, both MSCs and exosomes modified with MIR155HG were injected into a vein graft rat model via tail vein. We observed MSCs homing and intimal hyperplasia of vein graft using a fluorescent microscope and histological stain. Results Our study found that lncRNA MIR155HG promoted proliferation, migration, and anti-apoptosis of MSCs. NF-κB pathway took part in the regulation process induced by MIR155HG. OE-exo could enhance the activity and healing ability of HUVEC and reduce apoptosis. In vivo, OE-MSCs had a higher rate of homing to vascular endothelium. The combined treatment with OE-MSCs and OE-exo protected vascular endothelial integrity, reduced inflammatory cell proliferation, and significantly attenuated intimal hyperplasia of vein graft. Conclusion LncRNA MIR155HG could promote the survival and activity of MSCs, and reduce the apoptosis of HUVECs using exosome delivery. Exploiting MSCs and exosomes modified with MIR155HG could attenuate vein graft intimal hyperplasia more effectively and maximize the surgical effect.

Improved therapeutic effects on vascular intimal hyperplasia by mesenchymal stem cells expressing MIR155HG that function as a ceRNA for microRNA‐205

“…The external jugular vein was removed from the SD rat and connected to the infrarenal abdominal aorta in the same rat using the cuff technique. 13 MSCs (1 × 10 6 ) were injected into the caudal vein 24 h after surgery. Rats were humanely sacrificed 4 weeks later.…”

“…A study confirms that homing MSCs participate in endothelial repair and inhibit IH through paracrine. 13 Another study reports that the repressor/ activator protein-1 (RAP1), also called Terf2ip, is essential to maintain the immunomodulatory and paracrine function of MSCs. 14 Long noncoding RNA (lncRNA) is a non-protein coding RNA molecule with a length of 200-100,000 nt mainly involved in transcription or post-transcriptional regulation, protein transport and mRNA degradation.…”

“…A study confirms that homing MSCs participate in endothelial repair and inhibit IH through paracrine. 13 Another study reports that the repressor/activator protein‐1 (RAP1), also called Terf2ip, is essential to maintain the immunomodulatory and paracrine function of MSCs. 14 …”

Mesenchymal Stem Cell-Derived Long Noncoding RNAs in Cardiac Injury and Repair

“…Sudden cardiac death risk has been linked to a functional indel polymorphism in the lncRNA MIR155 host gene (MIR155HG) [ 105 ]. Overexpression of lncRNA MIR155HG in MSCs enhanced their survival, migration, and antiapoptotic properties [ 70 ]. These protective effects extended to exosomes derived from MIR155HG-overexpressing MSCs, which improved the activity of human umbilical vein endothelial cells, mitigating intimal hyperplasia and ultimately protecting vascular endothelial integrity in a vein graft model using rats [ 70 ].…”