Showing papers by "Sai Kiang Lim published in 2023"
TL;DR: HuMSC-derived extracellular vesicles were locally administered in mice hindlimb following 80-Gy X-ray irradiation and animals were monitored at different time points as mentioned in this paper .
Abstract: Abstract This study aims to investigate the mechanisms of human mesenchymal stem cell-derived extracellular vesicles (HuMSC-EV)-induced proangiogenic paracrine effects after radiation injury. HuMSC-EV were locally administered in mice hindlimb following 80-Gy X-ray irradiation and animals were monitored at different time points. HuMSC-EV improved neovascularization of the irradiated tissue, by stimulating angiogenesis, normalizing cutaneous blood perfusion, and increasing capillary density and production of proangiogenic factors. HuMSC-EV also stimulated vasculogenesis by promoting the recruitment and differentiation of bone marrow progenitors. Moreover, HuMSC-EV improved arteriogenesis by increasing the mobilization of monocytes from the spleen and the bone marrow and their recruitment into the muscle, with a pro-inflammatory potential. Importantly, monocyte depletion by clodronate treatment abolished the proangiogenic effect of HuMSC-EV. The critical role of Ly6C(hi) monocyte subset in HuMSC-EV-induced neovascularization process was further confirmed using Ccr2 −/ − mice. This study demonstrates that HuMSC-derived EV enhances the neovascularization process in the irradiated tissue by increasing the production of proangiogenic factors, promoting the recruitment of vascular progenitor cells, and the mobilization of innate cells to the injured site. These results support the concept that HuMSC-EV might represent a suitable alternative to stem cells for therapeutic neovascularization in tissue repair.
5 citations
TL;DR: In this article , the mesenchymal stromal cells (MSCs) exosomes were used to mitigate potential regulatory concerns on the scalability and reproducibility in the preparations of MSC exosome, which were produced using a highly characterized MYC-immortalized monoclonal cell line.
2 citations
TL;DR: In this article , the authors investigated the wound healing and immunomodulatory effects of MSC-derived exosomes (MSC-exo) in corneal injury through an established rat model.
Abstract: Corneal scarring is a leading cause of worldwide blindness. Human mesenchymal stem cells (MSC) have been reported to promote corneal wound healing through secreted exosomes. This study investigated the wound healing and immunomodulatory effects of MSC-derived exosomes (MSC-exo) in corneal injury through an established rat model of corneal scarring. After induction of corneal scarring by irregular phototherapeutic keratectomy (irrPTK), MSC exosome preparations (MSC-exo) or PBS vehicle as controls were applied to the injured rat corneas for five days. The animals were assessed for corneal clarity using a validated slit-lamp haze grading score. Stromal haze intensity was quantified using in-vivo confocal microscopy imaging. Corneal vascularization, fibrosis, variations in macrophage phenotypes, and inflammatory cytokines were evaluated using immunohistochemistry techniques and enzyme-linked immunosorbent assays (ELISA) of the excised corneas. Compared to the PBS control group, MSC-exo treatment group had faster epithelial wound closure (0.041), lower corneal haze score (p = 0.002), and reduced haze intensity (p = 0.004) throughout the follow-up period. Attenuation of corneal vascularisation based on CD31 and LYVE-1 staining and reduced fibrosis as measured by fibronectin and collagen 3A1 staining was also observed in the MSC-exo group. MSC-exo treated corneas also displayed a regenerative immune phenotype characterized by a higher infiltration of CD163+, CD206+ M2 macrophages over CD80+, CD86+ M1 macrophages (p = 0.023), reduced levels of pro-inflammatory IL-1β, IL-8, and TNF-α, and increased levels of anti-inflammatory IL-10. In conclusion, topical MSC-exo could alleviate corneal insults by promoting wound closure and reducing scar development, possibly through anti-angiogenesis and immunomodulation towards a regenerative and anti-inflammatory phenotype.
1 citations
TL;DR: The International Society for Cell & Gene Therapy Scientific Signature Series event "Therapeutic Advances With Native and Engineered Human EVs" as discussed by the authors took place as part of the ICSG 2022 Annual Meeting, held from May 4 to 7, 2022 in San Francisco, California, USA.
1 citations
TL;DR: In this paper, exosomal CD73 activity was found to promote anti-inflammatory M2-like macrophages by catalyzing the production of adenosine, which then binds to A2A and A2B to activate AKT/ERK-dependent signaling pathways.
Abstract: Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations.
1 citations
TL;DR: In this paper , the authors investigated the cellular processes and molecular mechanisms modulated by mesenchymal stromal/stem cell (MSC) exosomes in dental pulp regeneration.
Abstract: Mesenchymal stromal/stem cell (MSC) therapies are currently being explored for dental pulp regeneration. As the therapeutic effects of MSCs in tissue repair are mediated mainly through the release of extracellular vesicles (EVs) including exosomes, we investigated here the cellular processes and molecular mechanisms modulated by MSC exosomes in dental pulp regeneration. Using dental pulp cell (DPC) cultures, we demonstrated that MSC exosomes could increase DPC migration, proliferation, and odontogenic differentiation. The enhancement of these cellular processes was mediated through exosomal CD73-mediated adenosine receptor activation of AKT and ERK signaling. Consistent with these observations, MSC exosomes increased the expression of dentin matrix proteins and promoted the formation of dentin-like tissue and bridge-like structures in a rat pulp defect model. These effects were comparable to that of mineral trioxide aggregate (MTA) treatment. MSC exosomes also yielded recellularized pulp-dentin tissues in the root canal of endodontically-treated human premolars, following subcutaneous implantation in the mouse dorsum. Together, our findings suggest that MSC exosomes could exert a multi-faceted effect on DPC functions including migration, proliferation and odontogenic differentiation to promote dental pulp regeneration. This study provides the basis for development of MSC exosomes as a cell-free MSC therapeutic alternative for pulp-dentin regeneration.
TL;DR: In this article , the authors evaluated whether the pro−fibrotic M2 macrophage polarization induced by mesenchymal stem/stromal cell small extracellular vesicles (MSC−sEVs) could worsen liver fibrosis.
Abstract: Mesenchymal stem/stromal cell small extracellular vesicles (MSC−sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC−sEV use is an important consideration. One concern is that MSC−sEVs have been shown to induce M2 macrophage polarization, which is known to be pro−fibrotic, potentially indicating contraindication in fibrotic diseases such as liver fibrosis. Despite this concern, previous studies have shown that MSC−sEVs alleviate high−fat diet (HFD)−induced non−alcoholic steatohepatitis (NASH). To assess whether the pro−fibrotic M2 macrophage polarization induced by MSC−sEVs could worsen liver fibrosis, we first verified that our MSC−sEV preparations could promote M2 polarization in vitro prior to their administration in a mouse model of NASH. Our results showed that treatment with MSC−sEVs reduced or had comparable NAFLD Activity Scores and liver fibrosis compared to vehicle− and Telmisartan−treated animals, respectively. Although CD163+ M2 macrophages were increased in the liver, and serum IL−6 levels were reduced in MSC−sEV treated animals, our data suggests that MSC−sEV treatment was efficacious in reducing liver fibrosis in a mouse model of NASH despite an increase in pro−fibrotic M2 macrophage polarization.
TL;DR: Yates et al. as discussed by the authors investigated the functional role of extracellular vesicles in physiology and pathology in vivo and found that intercellular communication processes are predominantly mediated by the interplay between EVs and cell-surface molecules.