PF-127 hydrogel plus sodium ascorbyl phosphate improves Wharton’s jelly mesenchymal stem cell-mediated skin wound healing in mice

Abstract

Background: Factors such as poor engraftment, retention, and survival of the transplanted stem cells are deemed to limit their therapeutic efficacy for wound regeneration. Hence, it is necessary to explore these issues in order to resolve them. In this study, we aim to investigate the role of Pluronic F-127 (PF-127) hydrogel plus antioxidant sodium ascorbyl phosphate (SAP) in enhancing Wharton's jelly mesenchymal stem cell (WJMSC)-mediated effectiveness on full-thickness skin wound healing in mice. Methods: First, the cytotoxicity of PF-127 and the biological effect of SAP on the survival of WJMSCs were tested in vitro using cell viability and proliferation assays. Next, a cell suspension containing WJMSCs, PF-127, and SAP was topically administered onto an 8-mm diameter excisional full-thickness wound bed. Eight days after transplantation, the mice were sacrificed and the skin tissue was excised for histological and immunohistochemical analysis. Finally, in vivo distribution of transplanted WJMSCs was traced to investigate cell engraftment and the potential therapeutic mechanism. Results: PF-127 was found to be cytotoxic to WJMSCs while SAP significantly improved the survival of PF-127embedded WJMSCs. When this combination was topically transplanted onto the wound bed, wound healing was facilitated and dermis regeneration was achieved on the 8th day after surgery, as evidenced by an increase in dermal thickness, newly developed hair follicles, and collagen fiber deposition accompanied by a reduction in scar width. Further, immunohistochemical analysis demonstrated a higher number of anti-inflammatory M2 macrophages, proliferating cells, and newly formed blood vessels in the WJMSCs/PF-127/SAP group relative to all other groups. In addition, in vivo tracking results revealed a highly enhanced engraftment of WJMSCs accumulated in the dermis in the WJMSCs/PF-127/SAP group. (Continued on next page)Conclusions: SAP significantly improves the survival of WJMSCs in PF-127 encapsulation. Further, PF-127 plus SAP is an effective combination that enhances WJMSC engraftment in the dermis, which then promotes full-thickness wound healing through potential M2 macrophage formation and angiogenesis.

Wharton’s jelly mesenchymal stem cells embedded in PF-127 hydrogel plus sodium ascorbyl phosphate combination promote diabetic wound healing in type 2 diabetic rat

“…The WJMSCs were isolated from human umbilical cord and identified as our previous study report [ 21 ]. The WJMSCs were seeded in 90% DMEM/F12 media with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (Gibco, Grand Island, NY) at 37 °C in an incubator with 5% CO 2 .…”

“…In order to reduce the toxicity of PF-127 to WJMSC, recent studies have showed that adding membrane-stabilizing agent steroid hydrocortisone and platelet-rich plasma can significantly increase MSCs survival in PF-127 [ 19 , 20 ]. In addition, our previous studies have shown that sodium ascorbyl phosphate (SAP) can greatly enhance the viability of WJMSCs carried by PF127 and promote skin wound healing in mice [ 21 ]. SAP is the sodium salt of ascorbic acid 2-phosphate which has high stability even on after long-term exposure to reactive oxygen species as well as aqueous solution [ 22 ].…”

Thermosensitive Injectable Chitosan/Collagen/β-Glycerophosphate Composite Hydrogels for Enhancing Wound Healing by Encapsulating Mesenchymal Stem Cell Spheroids

“… 37 In addition, the combination of the Pluronic F-127 hydrogel and Wharton’s jelly mesenchymal stem cells has been shown to have enhanced wound healing potential through potential M2 macrophage formation and enhanced angiogenesis. 38 Murphy et al demonstrated that the MSC spheroid-encapsulated fibrin hydrogel accelerated wound healing by enhanced secretion of bioactive factors to promote neovascularization and modulate the inflammatory milieu. 39 These results and ours suggested that combination therapy can provide a potential way for chronic wound treatment with high quality.…”

Ad-Dressing Stem Cells: Hydrogels for Encapsulation

“…Mesenchymal stem cells Collagen-Fibrin [22], CH-GP-HEC [25], PHEMA-APMA-PAMAM [45], L-PDMA-PNIPAAm [46], PEG-PNIPAAm [26], Alginate [23], PEGDA [49], Fibrin [34], Gelatin-HA [27], PPS-b-PDMA-b-PNIPAAm [30], Alginate-Gelatin [16], PEG-4MAL-IFN-γ [53], HA-MAP [18,40] Bone marrow mesenchymal stem cells PNIPAAm-PHEMA-AOLA-PEGMA-PFO [33], CS-MA-PEGDA [24], Alginate-g-PNIPAAm [21] Wharton's jelly mesenchymal stem cells Poloxamer 407-SAP [50] BMP-2 transduced bone marrow mesenchymal stem cells GelMA [20] Brain-derived neurotrophic factor-producing mesenchymal stem cells Alginate (ultrahigh viscous) [42] Adipose-derived stem cells Gelan gum-HA [15], Poloxamer 407 [51], Gelan gum [43], PNIPAAm-SWCNTs [39], Alginate [19], PEG [17] Telomerase-immortalized human adipose-derived stem cells Gelatin-Methacrylamide [29] Cardiosphere-derived cells PNIPAAm [35], PNIPAAm-PPAA-PHEMA-OTMC-PEGMA [36] Human cardiac stem cells PNIPAAm-PAA [37] Neural stem cells-dental pulp stem cells Alginate-Collagen [47], CS-MA [48] Induced pluripotent stem cell-derived neural progenitor cells CS-bFGF [32] Human embryonic stem cell derived-neural stem cells HA [44] Retinal stem cell-derived rods and neural stem and progenitor cells HA and methylecelluse [41] Table 2. Cont.…”

“…In the same manner, Deng et al investigated whether the combination of Pluronic F-127 with sodium ascorbyl phosphate as encapsulating biomaterials could affect the survival and healing properties of Wharton's jelly MSCs (WJMSCs) in an animal model of skin wound healing. Indeed, mice that received encapsulated WJMSCs inside Pluronic F-127 and sodium ascorbyl phosphate showed increased healing rates when compared to either non-encapsulated WJMSCs, Pluronic F-127-alone or sodium ascorbyl phosphate-alone encapsulated WJMSCs, as their dermis thickened, the number of hair follicles increased and the scarring decreased [50]. In another study, using alginate as the encapsulating biomaterial, Khatab et al showed that after the intra-articular injection of MSCs into the knee joints of rats, the survival rates of encapsulated MSCs were significantly higher compared to non-encapsulated cells.…”