Abstract
Injecting human mesenchymal stem cells (hMSCs) at wound sites is known to have a therapeutic effect; however, hMSCs have several limitations, such as low viability and poor engraftment after injection, as well as a potential risk of oncogenesis. The use of a conditioned medium (CM) was suggested as an alternative method for treating various wounds instead of direct hMSC administration. In addition to not having the adverse effects associated with hMSCs, a CM can be easily mass produced and can be stored for long-term, thereby making it useful for clinical applications. In general, a CM is collected from hMSCs with low passage number; whereas, the hMSCs with high passage number are usually discarded because of their low therapeutic efficacy as a result of reduced angiogenic factor secretion. Herein, we used a CM collected from high passage number (passage 12, P12) hMSCs treated with gold-iron nanoparticles (AuFe NPs). Our AuFe NPs were designed to release the iron ion intracellularly via endocytosis. Endosomes with low pH can dissolve iron from AuFe NPs, and thus, the intracellularly released iron ions up-regulate the hypoxia-inducible factor 1α and vascular endothelial growth factor (VEGF) expression. Through this mechanism, AuFe NPs improve the amount of VEGF expression from P12 hMSCs so that it is comparable to the amount of VEGF expression from low passage number (passage 6, P6), without treatment. Furthermore, we injected the CM retrieved from P12 MSCs treated with AuFe NPs in the mouse skin wound model (AuFe P12 group). AuFe P12 group revealed significantly enhanced angiogenesis in the mouse skin wound model compared to the high passage hMSC CM-injected group. Moreover, the result from the AuFe P12 group was similar to that of the low passage hMSC CM-injected group. Both the AuFe P12 group and low passage hMSC CM-injected group presented significantly enhanced re-epithelization, angiogenesis, and tissue remodeling compared to the high passage hMSC CM-injected group. This study reveals a new strategy for tissue regeneration based on CM injection without considering the high cell passage count.
Highlights
Human mesenchymal stem cells are known to have wound healing effects
According to the in vivo data, the appearance of wound sites revealed no significant difference at 14 days after the treatment among the three groups; the relative amount of involucrin and laminin positive signals increased in P6 Human mesenchymal stem cells (hMSCs) and AuFe NP-treated P12 hMSC compared to P12 hMSCs without treatment, which indicates improved internal tissue regeneration in the wound sites compared to P12 hMSCs without treatment
conditioned medium (CM) can be used as an alternative source for stem cell therapy, the therapies based on CM are limited, as stem cells with low passage number can secrete larger amounts of therapeutic
Summary
Human mesenchymal stem cells (hMSCs) are known to have wound healing effects. Paracrine factors secreted from the transplanted hMSCs spread to the dermis and epidermis through diffusion and accelerate wound healing [4]. Gold-iron nanoparticles (AuFe NPs) were employed to improve the secretion of paracrine factors from adult stem cells by controlling the cellular microenvironment via Fe ion delivery. It was conjectured that if Fe ions can be successfully delivered into hMSCs with high passage number using pH-sensitive AuFe NPs, hMSCs with high passage number might be able to secrete more paracrine factors compared to those without any treatment. Opμtmim).ization of AuFe NP Concentration for the Treatment of hMSCs, Based on Cytotoxicity and VEGF Gene Expression. HhMMSSCCss ttrreeaatteedd wwiitthh 55 μμgg//mmLL ooff AAuuFFee NNPP eexxhhiibbiitteedd eennhhaanncceedd VVEEGGFF eexxpprreessssiioonn ccoommppaarreedd ttoo hhMMSSCCss wwiitthhoouutt NNPP ttrreeaattmmeenntt. According to the in vivo data (qRT-PCR, wound closing ratio, and tissue staining), the appearance of wound sites revealed no significant difference at 14 days after the treatment among the three groups; the relative amount of involucrin and laminin positive signals increased in P6 hMSCs and AuFe NP-treated P12 hMSC compared to P12 hMSCs without treatment, which indicates improved internal tissue regeneration in the wound sites compared to P12 hMSCs without treatment
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