TABLE 1.
Application of perinatal cells in in vivo animal models of skin wound healing. Time points indicated in the “Outcome” column mean days (d), weeks (w) or hours (h) after treatment.
| Perinatal cells | |||||
|---|---|---|---|---|---|
| PnD cell type | Dosage | Application (carrier) | Wound type, animal | Outcome | References |
| hAEC | 3.54 × 10^6 cells/cm2 | Intradermal injection | Full-thickness, diabetic mouse | hAEC showed higher engraftment, better keratinocyte-transdifferentiation rates and accelerated wound healing (wound closure and re-epithelialization) than hASC (d28) | Jin et al. (2016) |
| Splint model | |||||
| hAFC, hAFSC | 1.59 × 10^4 cells/cm2 | Topical (polyester disks covered with collagen) | Full-thickness, rat | hAFC and hAFSC achieved accelerated wound closure, epithelization, collagen fiber production, angiogenesis and the disappearance of inflammatory cells compared to controls without cells (d14, d17, d21) | Yang et al. (2013) |
| hAFSC | 6.41 × 10^6 cells/cm2 | Intradermal/subcutaneous injection | Full-thickness, mouse | hAFSC showed a better keratinocyte-transdifferentiation and enhanced wound closure and early-stage repair of skin damage than fibroblasts and sham controls by creating a moderate inflammatory microenvironment (d21) | Sun et al. (2019) |
| 1.99 × 10^6 cells/cm2 | Intradermal/subcutaneous injection | Full-thickness, mouse | hAFSC enhanced re-epithelialization and collagen III contents and achieved lower numbers of myofibroblasts and less fibrotic scarring than PBS controls (best effects d14, after d21 no significance). hAFSC engrafted in the epidermis and dermis | Fukutake et al. (2019) | |
| hAMSC | 3.54 × 10^6 cells/cm2 | Intradermal injection | Full-thickness, diabetic mouse | hAMSC had higher engraftment and keratinocyte-transdifferentiation potential and induced a better healing potential (increased wound closure, re-epithelialization and cellularity) than ASC and fibroblasts (d7, d10 and d14) | Kim et al. (2012) |
| Splint model | |||||
| 0.597 × 10^6 cells/cm2 | Topical (Matrigel or Matriderm) | Full-thickness, mouse | In both application forms, hAMSC promoted neovascularization compared to control without cells. Matriderm/hAMSC enhanced wound closure (d8). Inhomogeneous distribution of Matrigel led to inadequate wound closure | Tuca et al. (2016) | |
| 0.995 × 10^6 cells/cm2 | Topical (Matriderm or PCL/PLA, with or without Matrigel) | Full-thickness, mouse | Matriderm and PCL/PLA were suitable as carriers for hAMSC. 3 days in vitro culture of scaffolds with hAMSCs without Matrigel before wound application is recommended. PCL/PLA showed higher cell adherence and counteract wound contracture (d14) | Vonbrunn et al. (2020) | |
| hUC-MSC | 0.22 × 10^6 cells/cm2 | Subcutaneous injection | Skin flap, mouse | hUC-MSC were mainly distributed in the subcutaneous flap tissues and increased survival of the flap, neovascularization and expression of bFGF and VEGF (d7) | Leng et al. (2012) |
| 1.99 × 10^6 cells/cm2 | Subcutaneous injection (SA/Col hydrogel) | Full-thickness, mouse | SA/Col hydrogel + hUC-MSC accelerated wound closure, formation of granulation, enhanced collagen deposition and angiogenesis. Hydrogel promoted the survival of hUC-MSC, enhanced growth factors secretion, and inhibited inflammation (d7, d14) | Zhang et al. (2021) | |
| 0.11 × 10^6 cells/cm2 | Subcutaneous injection | Radiation, rat | hUC-MSC increased neovascularization and re-epithelization (d14, d21, d28) | Liu et al. (2018) | |
| 2.83 × 10^6 cells/cm2 | Subcutaneous injection | Full-thickness, diabetic rat | Compared to un-transduced hUC-MSC, c-Jun overexpressing hUC-MSC accelerated wound closure, enhanced angiogenesis and re-epithelialization (d7, d10, d15, d17) | Yue et al. (2020) | |
| 1.27 × 10^6 cells/cm2 | Topical (collagen-based scaffolds, Integra® and Col) | Full-thickness, mouse | hUC-MSC accelerated angiogenesis compared to ASC and control without cells (d7, d10) and provided a suitable matrix for wound repair, without altering the inflammatory response in the animals | Edwards et al. (2014) | |
| 0.44 × 10^6 cells/cm2 | Topical (collagen membrane) | Full-thickness, mouse | HOXA4-overexpressing hUC-MSC differentiated into epidermal cells and increased re-epithelialization of wounds and thickness of the epidermis (d7, d14, d21) | He et al. (2015) | |
| Not specified | Topical (collagen membrane or collagen-fibrin membrane) | Full-thickness, mouse | hUC-MSC promoted wound healing. Collagen-fibrin carriers for hUC-MSC were more efficient in wound healing than collagen membrane carriers (d5, d10, d15) | Nan et al. (2015) | |
| 0.339 × 10^6 cells/cm2 | Topical (fibrin-based scaffold) | Full-thickness, mouse | Fibrin-based scaffolds with hUC-MSC healed slowly with no scarring. Untreated wounds or wounds treated with scaffolds without cells healed rapidly but disorderly, due to wound retraction into scarring (d15, d21, d36) | Montanucci et al. (2017) | |
| 1.99 × 10^6 cells/cm2 | Topical (PF-127/SAP hydrogel) | Full-thickness, mouse | PF-127/SAP hydrogel enhanced engraftment of hUC-MSC in the dermis and facilitated dermis regeneration (increase in thickness, collagen fibers, hair follicles), angiogenesis and M2 macrophage formation (d8) | Deng et al. (2020) | |
| 1.77 × 10^6 cells/cm2 | Topical (collagen scaffold) | Full-thickness, diabetic mouse Splint model | Combination of hUC-MSC therapy and hyperbaric oxygen had a collaborative effect on wound-healing, with a faster healing rate compared to hUC-MSC alone (d7) | Pena-Villalobos et al. (2018) | |
| 0.39 × 10^6 cells/cm2 | Topical (cell spray) | Burn 3rd degree, rat | hUC-MSC increased re-epithelialization compared to control without cells. hUC-MSC were detected in the burned areas at d7, d14, d21 | Pourfath et al. (2018) | |
| Not specified | Topical (collagen–chitosan laser drilling acellular dermal matrix) | Full-thickness, diabetic rat | hUC-MSC accelerated wound healing by activation of the Wnt signaling pathway (d7, d14, d21) | Han et al. (2019) | |
| 200 cells/cm2 | Topical (Integra® collagen-based scaffold) | Burn full-thickness, pig | Low dose hUC-MSC regenerated wounds most efficaciously. Best effects were achieved by 40,000 cells/cm2 (accelerated epithelialization and vascularization, reduced signs of scarring, fibrosis, reduced numbers of macrophages compared to controls (d28) | Eylert et al. (2021) | |
| 5,000 cells/cm2 | |||||
| 40,000 cells/cm2 | |||||
| 200,000 cells/cm2 | |||||
| 400,000 cells/cm2 | |||||
| 2000,000 cells/cm2 | |||||
| 0.1 × 10^6 cells/cm2 | Topical (PVA hydrogel membrane) | Non-healing skin lesions, dog | hUC-MSC induced a significant progress in skin regeneration with decreased extent of ulcerated areas | Ribeiro et al. (2014) | |
| 29 × 10^6 cells/kg | Intravenous injection | Full-thickness, diabetic rat | UC-MSC were detectable in the wound tissue (d16). They improved wound healing by regulating inflammation, trans-differentiation and providing growth factors that promote angiogenesis, cell proliferation and collagen deposition (d8, d16) | Shi et al. (2020) | |
| 25 × 10^6 cells/kg | Intravenous injection | Burn full-thickness, rat | hUC-MSC were detectable in the wound tissue for 3 weeks. They accelerated wound healing (wound closure, vascularization, collagen deposition) and decreased inflammation (w2, w3, w6, w8) | Liu et al. (2014) | |
| 25 × 10^6 cells/kg | Intravenous injection | Burn full-thickness, rat | hUC-MSC attenuated burn-induced excessive inflammation via secretion of ant-inflammatory protein TSG-6 which inhibits activation of P38 and JNK signaling (6, 12, 24, 48 h) | Liu et al. (2016) | |
| a) hUC-MSC-Fib | Not specified | Topical collagen-chitosan acellular dermal matrix - tissue engineered dermis (TED) | Full-thickness, pig | me-VEGF-hUC-MSC-Fib improved the vascularization of tissue-engineered dermis and induced a higher wound healing than controls (me-hUC-MSC, empty capsule and PBS-treated group) (w3) | Han et al. (2014) |
| b) me-VEGF- hUC-MSC-Fib | |||||
| a) hUC-MSC | 5.09 × 10^6 cells/cm2 | (a-b) Intradermal injection | Full-thickness, mouse | Transplantation of celecoxib (anti-inflammatory drug) -preconditioned hUC-MSC-End showed higher wound healing potential than hUC-MSC and hUC-MSC-End (d7) | Kaushik and Das, (2019) |
| b) hU-MSC-End | Splint model | ||||
| hPMSC | 45 × 10^6 cells/kg | Intraperitoneal and intradermal injection | Full-thickness, mouse | hPMSC enhanced wound healing through release of proangiogenic factors and decreased proinflammatory cytokines. The intraperitoneal injections are more effective than intradermal injections (d7) | Abd-Allah et al. (2015) |
| 1.99 × 10^6 cells/cm2 | Subcutaneous injection | Full-thickness, diabetic rat | hPMSC accelerated wound closure, increased collagen deposition, granulation tissue and epidermis thickness (d15). Wound healing was accelerated by decrease of local pro-inflammatory cytokines TNF-α, IL-6 and IL-1, increase of anti-inflammatory IL-10 | Wang et al. (2016) | |
| 5.09 × 10^6 cells/cm2 | Topical (Matrigel) | Full-thickness, mouse | PDGFR-β- hPMSC displayed a superior angiogenic property and exerted enhanced therapeutic efficacy on cutaneous wound healing compared to PDGFR-β -negative hPMSC (d7, d14) | Wang et al. (2018) | |
| Splint model | |||||
| hUC-PVC | 7.96 × 10^6 cells/cm2 | Topical (fibrin gel) | Full-thickness, mouse | hUC-PVC accelerated re-epithelization and dermal repair and wound strength compared to treatment without cells (d7) | Zebardast et al. (2010) |
| 1.27 × 10^6 cells/cm2 | Topical (decellularized dermal matrix scaffold) | Full-thickness, diabetic rat | hUC-PVC accelerated wound closure rate (faster re-epithelization, more granulation tissue formation, decreased scarring and increased neovascularization than treatment without cells (d14, d21) | Milan et al. (2016) | |
| a) hAEC-Ker | a) 7,500 cells/cm2 | Topical (plasma-based gel) | Burn 2nd degree, full-thickness excision, rat | Scaffolds seeded with hUC-MSC-Fib and hAEC-improved re-epithelization concurrent with reduced apoptosis compared to treatment without cells (d10, d20) | Mahmood et al. (2019) |
| + b) hUC-MSC-Fib | b) 6,250 cells/cm2 | ||||
| a) hAMSC | 0.6 × 10^6 cells/cm2 | (a-c) Topical (Matriderm) | Full thickness, mouse | hAMSC, hCP-MSC-bv and hUC-MSC induced faster wound healing and vascularization compared to controls without cell treatment (d8). hCP-EC co-application did not further improve the advantageous effects of MSC. | Ertl et al. (2018) |
| b) hCP-MSC-bv | |||||
| c) hUC-MSC | |||||
| +co-application with hCP-EC | |||||
Abbreviations: bFGF, basic fibroblast growth factor; coI, collagen type I; hAEC, human amniotic membrane epithelial cells; hAEC-Ker, human amniotic membrane epithelial cells derived keratinocytes; hAFC, human amniotic fluid cells; hAFSC, human amniotic fluid stem cells; hAMSC, human amniotic membrane mesenchymal stromal cells; hASC, human adipose mesenchymal stromal cells; hCP-EC, human chorionic plate endothelial cells; hCP-MSC-bv, human chorionic plate mesenchymal stromal cells derived from blood vessels; hPMSC, human placenta mesenchymal stromal cells; hUC-MSC, human umbilical cord mesenchymal stromal cells; hU-MSC-End, human umbilical cord mesenchymal stromal cells -endothelial transdifferentiated; hUC-MSC-Fib, human umbilical cord mesenchymal stromal cells derived fibroblasts; hUC-PVC, human umbilical cord perivascular cells; me-VEGF- hUC-MSC-Fib, microencapsulated VEGF-gene modified human umbilical cord mesenchymal stromal cells derived fibroblasts; PCL/PLA, Poly(caprolactone)/poly(l-lactide); PDGFA, platelet derived growth factor A; PDGFR-β, platelet derived growth factor receptor β; PF-127/SAP, Pluronic F-127 hydrogel plus antioxidant sodium ascorbyl phosphate; PVA, polyvinyl alcohol; SA, sodium alginate; TED, Topical collagen-chitosan acellular dermal matrix - tissue engineered dermis; TNF-α, tumor necrosis factor α; TSG-6, TNF-stimulated gene 6 protein; VEGF, vascular endothelial cell growth factor; IL-1, IL-6, IL-10, interleukin-1, -6, -10.