N-desulfated and reacetylated modification of heparin modulates macrophage polarization.

Heparin as a widely used anticoagulant drug has potent anti-inflammatory effects, which have been rarely reported to be involved in macrophage polarization. Furthermore, the effects of structural modifications of heparin on the plasticity of macrophage functions have not been clearly understood. In this study, the N-desulfated reacetylated derivative of heparin (NDeSAcH) was prepared and its immunoregulatory effects of macrophage polarization were evaluated. The findings indicated that NDeSAcH could effectively promote the release of more nitric oxide (NO), interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) in RAW264.7 cells than heparin. Moreover, the production of NO, IL-6 and TNF-α was significantly inhibited by NDeSAcH in LPS-induced RAW264.7 cells, while the secretion of transforming growth factor-ß (TGF-ß) was suppressed in M2 macrophages. The N-desulfated and reacetylated group of heparin was proved to have two-side adjusting effects on the polarization of macrophages. This study suggested that NDeSAcH might be a promising candidate for modulating macrophage polarization and treating inflammation-related diseases.

Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Accelerate Diabetic Wound Healing via Promoting M2 Macrophage Polarization, Angiogenesis, and Collagen Deposition.

Some scholars have suggested that the clinical application of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) might represent a novel strategy to improve diabetic wound healing. However, the mechanisms underlying the effects of hucMSCs-exo on wound healing remain poorly understood. This study aimed to identify the mechanism of hucMSCs-exo in treating diabetic wounds. HucMSCs-exo were isolated from human umbilical cord mesenchymal stem cells (hucMSCs) and subcutaneously injected into full-thickness wounds in diabetic rats. Wound healing closure rates and histological analysis were performed. The levels of tumor necrosis factor-α (TNF-α), macrophage mannose receptor (MMR/CD206), platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. The degree of collagen deposition was examined using Masson's trichrome staining. Gross evaluation of wound healing was carried out from day 0 to 14 post-surgery, and the wound site was harvested for histology on days 3, 7, and 14 post-wounding. HucMSCs-exo transplantation increased diabetic wound healing. In vitro, hucMSCs-exo promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and NIH-3T3 cells. In vivo, hucMSCs-exo reduced wound area and inflammatory infiltration and increased collagen fibers. In addition, wound tissues in the hucMSCs-exo group had higher CD206, CD31, and VEGF expressions and lower TNF-α levels than those in the control group on day 14. Our results demonstrated that hucMSCs-exo facilitated diabetic wound repair by inducing anti-inflammatory macrophages and promoting angiogenesis and collagen deposition.

Heparan sulfate analogues regulate tumor-derived exosome formation that attenuates exosome functions in tumor processes.

Heparan sulfate (HS) is involved in many biological activities, including the biogenesis and uptake of exosomes, which are related to the occurrence and development of tumors. This study investigated the role of HS analogues (heparin, low molecular weight heparin, and 6-O-desulfated heparin) in modulating exosome secretion, composition and functions. Exosomes derived from B16F10 cells exposed to different HS analogues were isolated and characterized by TEM, western blotting and Nanosight analyses. The number, size and protein cargo of exosomes secreted by HS analogues-induced B16F10 cells were detected. The findings indicated the reduced tumor-derived exosome secretion and protein cargo as reflected by lower levels of CD63, TSG101, heparinase and IL-6 in exosomes derived from heparin-induced B16F10 cells as compared with 6-O-desulfated heparin-induced tumor cells. Further functional assays demonstrated that exosomes from tumor cells exposed to heparin weakened tumor proliferation, migration and invasion most significantly among various exosomes derived from B16F10 cells treated with different HS analogues. Moreover, the sulfate group at 6-O position of heparan sulfate has been proved to play an important role in tumor-derived exosome formation and functions. This study suggested a vital view to develop more specific and efficient HS-based strategies in cancer treatment for targeting tumor-derived exosomes.

Adult mesenchymal stem cells and their exosomes: Sources, characteristics, and application in regenerative medicine.

Human mesenchymal stem cells (MSCs) have become a hot topic in the development of cell therapies and bioengineering. All kinds of MSCs are genomic stable and have the self-renewal ability. Main sources of MSCs are bone marrow, adipose tissues, umbilical cord and placental tissues. MSCs can be cultured in many undifferentiated passages to grow into more specialized cells, produce secretory factors and also support trophic functions in the body. Exosomes, derived from MSCs also have great potential in regenerative medicine and tissue engineering. Exosomes are secreted by MSCs and have the same therapeutic potential as their parent cells. MSCs and their exosomes combined with biomaterials can also be more effective in promoting the regeneration of tissues and organs. However, for use of MSCs-exosomes as a clinical agent different MSCs-exosomes have been manufactured and their therapeutics effects demonstrated in clinical studies. But there are still many characteristics which are unknown and many barriers still need to be conquered. In this review, we not only highlighted the characteristics of human MSCs and their exosomes, but also provided their latest therapeutic strategies in regenerative medicine.

Protective effect and mechanism of polysaccharide from Dictyophora indusiata on dextran sodium sulfate-induced colitis in C57BL/6 mice.

Polysaccharide (DIP) from Dictyophora indusiata has showed noteworthy anti-inflammatory activities. Given that the closely relationship between inflammation and ulcerative colitis, we speculated that DIP may alleviate ulcerative colitis. However, there was not any report about the effect of DIP on this disease. The purpose of this paper is to explore the protective effect and mechanism of DIP on DSS-induced colitis in C57BL/6 mice. The data indicated that DIP could improve DSS-induced colitis by restoring intestinal barrier function and regulating macrophage polarization. Its mechanism was found to be associated with decreased oxidative stresses and inflammation, suppressive key signal pathways related with colitis, improved the expression of tight junction proteins and down-regulated M1 macrophage polarization. The results suggested that DIP could be served as an agent for improving intestinal inflammation in functional foods or nutraceutical formulations.