TABLE 2.
Application of perinatal cell-conditioned medium (CM) alone or compared to/combined with perinatal cells in in vivo animal models of skin wound healing. Time points indicated in the “Dosage” and Outcome” columns mean days (d), weeks (w) or hours (h) of/after treatment.
| Perinatal cell-conditioned medium (CM) | |||||
|---|---|---|---|---|---|
| PnD | Dosage | Application (carrier) | Wound type, animal | Outcome | References |
| hAEC-CM | 100 μl (48 h) CM/cm2 on d1 and d3 | Subcutaneous injection | Full-thickness, mouse | hAEC-CM enhanced wound healing (closure, tissue reorganization, replacement of skin appendages), whereas CM+ ERK, JNK and AKT- inhibitors impaired wound healing (d7, d14). Control mice received PBS injection | Zhao et al. (2016) |
| hPMSC-CM | 31.85 μl (72 h) CM/cm2 | Subcutaneous injection | Burn degree n.d., mouse | hPMSC were maintained in normoxic or hypoxic conditions. Hypoxic CM reduced scar formation, while there was no marked difference between normoxic CM and controls (normal medium) at d8 | Du et al. (2016) |
| hUC-MSC-CM | 50 μl (5 μg/ml) (48 h) CM/cm2 every 2nd d for 8w | Topical (hydrogel) | Radiation, rat | Hydrogel containing hUC-MSC-CM accelerated wound closure, sebaceous gland cell-like regeneration and angiogenesis compared to EGF gel and negative control (w2, w4, w6, w8, wound treatment every 2 days) | Sun et al. (2019) |
| (48 h) CM (volume not specified) | Topical (SA/gelatin hydrogel) | Full-thickness, rat | Hydrogel containing CM of UC-MSC transfected cells accelerated wound contraction and promoted neovascularization, skin-appendages, epithelialization compared to control (PBS or Hydrogel treatment without CM (d14) | Sabzevari et al. (2020) | |
| Splint model | |||||
| Perinatal cell-conditioned medium (CM) compared to/or combined with perinatal cells | |||||
| PnD | Dosage (CM harvesting time) | Application (carrier) | Wound type, animal | Outcome | References |
| a) hAMSC | 2.546 × 10^6 cells/cm2 | Subcutaneous injection | Burn 2nd degree, mouse | hAMSC and hAMSC-CM similarly accelerated re-epithelialization and cell proliferation compared to controls without cells or CM (d7, d14, d21), increased expression of CK19 and PCNA, inhibited heat stress-induced apoptosis through activating PI3K/AKT signaling pathway | Li et al. (2019) |
| b) hAMSC-CM | 254.6 μl (48 h) CM/cm2 | ||||
| a) hAEC-CM | I exp. 7 μl (72 h) CM/cm2 d1, d7 | Topical (cell spray) | Burn partial-thickness, guinea pig | hAEC, hAEC-CM, or the combination of both improved epithelialization compared to controls without cell or CM treatment (d7 – d21). Frequent application of hAEC-CM for every day achieved better results than 2-fold application at d0 and d7 | Payne et al. (2010) |
| b) hAEC + hAE-CM | 33,333 cells/cm2 d1, d7 | ||||
| c) hAEC + unconditioned medium | II exp. 10 μl (72 h) CM/cm2 on every 2nd d or 4th d or 7th d for 3w | ||||
| a) hUC-MSC | 7.07 × 10^6 cells/cm2 | (a-b) Subcutaneous injection | Full-thickness, diabetic mouse | hUC-MSC and hUC-MSC-CM accelerated wound closure and angiogenesis, with similar effects at d10. CM induced better effects in wound healing and higher expression of PDGFß and KGF in wounds at d14 | Shrestha et al. (2013) |
| b) hUC-MSC-CM | 212.3 μl (24 h) CM/cm2 | ||||
| a) hUC-MSC or hU-MSC-End | 1.77 × 10^6 cells/cm2 | (a-b) Intradermal injection | Full-thickness, mouse Splint model | hUC-MSC and CM accelerated wound closure, regeneration capacity and neovascularization. hUC-MSC-End achieved better cellular and paracrine effects than hUC-MSC (d7, d12). Effects of cells were not directly compared to the effects of CM. | Aguilera et al. (2014) |
| b) hUC-MSC-CM or hU-MSC-End-CM | 212.3 μl (48 h) CM/cm2 | ||||
| a) hUC-MSC | 1.99 × 10^6 cells/cm2 | (a-b) Subcutaneous injection | Full-thickness, diabetic mouse | hUC-MSC and hUC-MSC-CM similarly improved angiogenesis, re-epithelialization and granulation (d14). Fibroblasts or PBS served as controls | Zhang et al. (2020) |
| b) hUC-MSC-CM | 298 μl (24 h) CM/cm2 | ||||
| a) hUC-MSC | 1.99 × 10^6 cells/cm2 3.54 × 10^6 cells/cm2 199 μl (72 h) CM/cm2 354 μl (72 h) CM/cm2 | (a-b) Topical (AV/PCL scaffold) or subcutaneous injection | Full-thickness, diabetic mouse | hUC-MSC and hUC-MSC-CM applied by AV/PCL carrier or subcutaneous injection similarly achieved better effects on wound healing (re-epithelialization, collagen deposition, angiogenesis and immunomodulation) than controls (fibroblasts, fibroblast-CM, unconditioned medium (d7, d14, d28) | Raj et al. (2019) |
| b) hUC-MSC-CM | |||||
| a) hUC-MSC | 6.37 × 10^4 cells/cm2 | Topical (alginate gel) with cells or CM | Full-thickness, mouse Splint model | hUC-MSC-alginate and hUC-MSC-CM-alginate achieved faster wound healing than control groups (FBS-alginate, PBS-alginate), (d10, d15) | Wang et al. (2016) |
| b) hUC-MSC-CM | |||||
| a) hUC-PVC | 3.54 × 10^6 cells/cm2 | (a-b) Intradermal injection combined with topical application | Full-thickness, mouse Splint model | hUC-PVC and hUC-PVC-CM accelerated wound closure and healing (collagen deposition and angiogenesis) compared to fibroblasts and fibroblast-CM (d4, d7, d14). Effects of cells were not directly compared to the effects of CM. | Shohara et al. (2012) |
| b) hUC-PVC- CM | 354 μl (48 h) CM/cm2 | ||||
Abbreviations AV/PCL, Aloe vera/po lycaprolactone; hAEC, human amniotic membrane epithelial cells; hAMSC, human amniotic membrane mesenchymal stromal cells; 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-PVC, human umbilical cord perivascular cells; CM, conditioned medium derived from hAEC, hAMSC, hPMSC, hUC-MSC, hUC-MSC-End, hUC-PVC; SA, sodium alginate.