Table 1.
Summary of studies on the role of mesenchymal stem cells in preclinical models of systemic sclerosis.
| Model/species | Number and origin of MSCs | Route of injection | Injection time | Main results | Mechanisms | References |
|---|---|---|---|---|---|---|
| Bleomycin intratracheal/mouse | 5 × 105 allogenic BM-MSCs | IV | d0 or d7 | Reduction of collagen content and inflammation in lungs after treatment at d0 | ND | (25) |
| Bleomycin intratracheal/mouse | 5 × 105 syngeneic BM-MSCs | IV | H6 | Reduction of inflammation and fibrosis in lungs | Differentiation into distinct lung cell phenotypes | (26) |
| Bleomycin intratracheal/mouse | 5 × 105 syngeneic BM-MSCs | IV | d3 | Reduction of collagen content and inflammation in lungs | ND | (27) |
| Bleomycin intratracheal/rat | 5 × 106 syngeneic BM-MSCs | IV | H12 | Reduction of TGFβ1, PDGF-A, PDGF-B, IGF1 and collagen content in lungs | MSC differentiation into alveolar epithelial cells | (28) |
| Bleomycin intratracheal/rat | 1 × 106 syngeneic BM-MSCs | IV | d4 | Diminution of inflammation, collagen content, angiogenic markers and nitric oxide metabolites in lungs | ND | (29) |
| Bleomycin subcutaneous/mouse | 1 × 106 syngeneic BM-MSCs | SC | Daily injection during 4 weeks | Improvement remodeling matrix responsible for normal collagen arrangement in skin. Reduction of inflammation and α-sma-positive myofibroblasts | Down-regulation of TGFβ, type I collagen and HSP47 expression | (30) |
| Bleomycin intranasal/mice | 1 × 106 human UC-MSCs | IV | d1 | Reduction of inflammation, collagen content and TGFβ expression and improvement remodeling of matrix | ND | (31) |
| Bleomycin intratracheal/mouse | 4 × 106 IP or 1 × 106 IV ou IT xenogeneic & allogeneic amnion- and chorion-derived fetal MSCs | IP or IV or IT | d0 | Reduction of lung fibrosis | ND | (32) |
| Bleomycin intratracheal/mouse | 1 × 106 murine amniotic fluid MSCs | IV | d0 or d14 | Inhibition of collagen deposition and preservation of pulmonary function | ND | (33) |
| Bleomycin intranasal/mouse | Human BM-MSCs or amnion-derived MSCs | IV | d0 and d7 | Reduction of inflammation and collagen content in lungs | ND | (34) |
| Bleomycin intratracheal/mouse (every 2 weeks, 8 doses in total) | 5 × 105 human ASCs | IP | 4 doses at time of bleomycin injection | Reduction of lung fibrosis and inflammation | ND | (35) |
| Bleomycin intravenous/rat | 5 × 105 syngeneic BM-MSCs | IV | d1 or d7 | Reduction of lung fibrosis only after treatment at d1 | ND | (36) |
| Bleomycin intratracheal/rat | 2.8 × 106 or 5.6 × 106 human BM-MSCs /kg | IV | d8 or d15 | Safety of MSC injection No amelioration of disease | ND | (37) |
| Bleomycin intratracheal/rat | Autologous ASCs | IT | d15 | No improvement but prevention of lung damage aggravation | ND | (38) |
| Bleomycin intratracheal/mouse | 5 × 105 syngeneic BM-MSCs | IV | d1 or d3 or d6 | Reduction of lung inflammation & fibrosis after d3 or d6 treatment | ND | (39) |
| Bleomycin intratracheal/mouse | 5 × 105 syngeneic ASCs from old or young mice | IV | d1 | Only young ASCs induced lower lung fibrosis, oxidative stress and apoptosis | Lower levels of MMP-2, IGFR and AKT activation | (40) |
| Bleomycin intratracheal/mouse | 5 × 105 syngeneic ASCs | IV | d1 | Reduction of lung & skin fibrosis Acceleration of wound healing | Decreased miR-199-3p and increased caveolin-1 in lungs and skin | (41) |
| HOCl intradermic injection/mouse (daily, 42 days) | 2.5 × 105 syngeneic or allogeneic BM-MSCs, or human ASCs & BM-MSCs | IV | d0 or d21 | Reduction of fibrotic, inflammatory and oxidative markers in skin & lungs. Improvement of matrix remodeling. | ND | (43) (44) (45) |
| Tsk1/+ mouse | 1 × 105 allogenic BM-MSC /kg bodyweight | IV | 8 weeks | Improvement of osteopenia | Downregulation of the IL4R pathway by miR-151-5p in MSC-EV | (47) |
| Bleomycin intratracheal/rat | 2.5 × 106syngeneic BM-MSCs | IV | d0 or d7 | Reduction of alveolitis, pulmonary fibrosis and oxidative stress | Conversion of BM-MSC into type II alveolar epithelial cells | (48) |
| Bleomycin intratracheal/rat | 0.2mL allogenic BM-MSC supernatants | IT | H6 and d3 | Reduction of collagen content, inflammation and fibrosis in lungs | ND | (49) |
| Bleomycin intratracheal/mouse | 5 × 105 allogenic BM-MSCs | IV | d0 | Reduction of IL1α lung level | IL1RN expressing MSCs antagonizing IL1α | (50) |
| Bleomycin intranasal/mice | 5 × 104 allogenic or HGF KO BM-MSCs/g bodyweight | IV | H6 or d9 | Reduction of lung fibrosis and inflammation, and increase of HGF | HGF release | (51) |
| Bleomycin intratracheal/mouse | 2.5 × 105 syngeneic OSM- preconditioned BM-MSCs | IT | d3 | Diminution of inflammation and fibrosis in lungs and improvement of respiratory function | Production of high level of HGF | (52) |
| Bleomycin intratracheal/mouse | 2.5 × 105 syngeneic hypoxia-preconditioned BM-MSCs | IT | d3 | Improvement of lung function and matrix remodeling. Decreased pro-inflammatory and fibrotic factors in lungs | Anti-apoptotic | (53) |
| Bleomycin intratracheal/mouse | 2 × 105 NAC-pretreated human embryonic MSCs | IV | d1 | Decrease of inflammation and lung fibrosis. | Increased antioxydative capacity of MSCs | (54) |
| Bleomycin intratracheal/mouse | 5 × 105 human BM-MSCs overexpressing let7d | IV | d7 | Reduction of collagen content and inflammation in lungs | Let7d over-expression | (55) |
| Bleomycin intratracheal/mouse | 1 × 106 xenogenic UC-MSCs over-expressing ACE2/kg bodyweight | IV | d3 | Decrease of collagen content, fibrotic and pro-inflammatory factors and increase of anti-oxidative mediators | ACE2 over-expression | (56) |
| Bleomycin subcutaneous/mice (daily, 21 days) | 1 × 106 Trx-1-overexpressing BM-MSCs | SC | Daily | Reduction of skin fibrosis and apoptosis, promotion of BM-MSC survival and differentiation into endothelial cells | TRX1-mediated inhibition of oxidative stress | (57) |
ACE2, angiotensin converting enzyme 2; AKT, protein kinase B; ASCs, adipose tissue-derived mesenchymal stem cells; BM-MSCs, bone marrow mesenchymal stem cells; HGF, hepatocyte growth factor; HOCl, hypochlorite; IGF, insulin growth factor; IGFR, IGF receptor; IL, interleukin; IL1RN, interleukin 1 receptor antagonist; IP, intraperitoneal; IT, intratracheal; IV, intraveinous; KO, knock-down; MMP, metalloproteinase; MSC-EV, mesenchymal stem cell-derived extracellular vesicles; NAC, N-acetylcystein SC, subcutaneous; OSM, onconstatin M; PDGF, platelet-derived growth factor; TGFβ, transforming growth factor; Trx-1, thioredoxin 1; Tsk1, tight skin; UC-MScs, umbilical cord-derived mesenchymal stem cells.