Management of Fibrosis: The Mesenchymal Stromal Cells Breakthrough

Table 4

MSC treatment on preclinical pulmonary fibrosis models.

References	Organism	Model	Treatment	MSC source	Timing	Quantity	Route	Outcome
[67]	Mouse	Bleomycin	0.15 mg bleomycin administered intranasally	UC	24 h after bleomycin inhalation	10^6 cells	Tail vein	(i) Decreased expression of IL-10, IFN-γ, and TNF-α; (ii) Decreased concentration of TGF-β1; (iii) Decreased concentration of pSmad2; (iv) Decreased expression of collagen 1α1; (v) Increased concentration of active MMP-2; (vi) Decreased expression of TIMP-1, TIMP-2, TIMP-3, and TIMP-4
[68]	Mouse	Bleomycin	4 U/kg bleomycin instilled in the tracheal lumen	BM	Immediately following or 1 week after bleomycin inhalation	5.10^5 cells	Jugular vein	(i) Reduced collagen concentration (best effect when MSCs are transplanted immediately after bleomycin treatment); (ii) Decreased expression of MMP-2, MMP-9, and MMP-13
[69]	Mouse	Silica	200 𝜇g/kg twice (day 1 and 4 weeks later) by intratracheal injection	Human BM	12 and 14 weeks after first silica injection	2.10^5 cells or 10 𝜇g of MSC microvesicles	Tail vein	Bronchoalveolar lavage: (i) Reduced number of neutrophils; (ii) Reduced number of lymphocytes; (iii) Reduced number of macrophages (not significant after microvesicle injection); Lung samples: (i) Reduced fibrotic area (not significant after microvesicle injection); (ii) Reduced concentration of collagen I; (iii) Reduced concentration of α-SMA (not significant after microvesicle injection)
[70]	Rat	Bleomycin	3 mg/kg bleomycin instilled intranasally	BM	4 days after bleomycin inhalation	10^6 cells	Tail vein	Bronchoalveolar lavage: (i) Reduced number of neutrophils; (ii) Reduced number of lymphocytes; (iii) Reduced number of macrophages; (iv) Decreased expression of IL-6 and TNF-α; Lung samples: (i) Reduced fibrotic area; (ii) Decreased expression of IL-1β; (iii) Decreased expression of TGF-β; (iv) Decreased expression of VEGF; (v) Decreased concentration of RNS
[71]	Rat	Bleomycin	5 mg/kg intratracheal perfusion	BM	12 h after bleomycin inhalation	5.10^6 cells	Tail vein	(i) Reduced fibrotic area; (ii) Decreased expression of TGF-β1; (iii) Decreased expression of PDGF-A (/1.4) and PDGF-B; (iv) Decreased expression of IGF-1; (v) MSCs differentiated in alveolar epithelial cells
[72]	Rat	Bleomycin	1.28 U instilled intratracheally	BM transfected with HGF expression plasmid	7 days after bleomycin instillation	3.10^6 cells	Intratracheal instillation	(i) Reduced Ashcroft score (fibrosis scoring); (ii) Reduced collagen concentration; (iii) Transfected cells yield better results

Influence of fibrosis induction methods, MSC source, timing of injection, quantity of MSCs transplanted, and transplantation route. Outcomes are expressed compared to control groups (i.e. groups treated but not transplanted with MSCs) unless stated otherwise (α-SMA: α-smooth muscle actin; BM: bone marrow; HGF: hepatocyte growth factor; IGF: insulin-like growth factor; IL: interleukin; MMP: matrix metalloproteinase; MSC: mesenchymal stromal cell; PDGF: platelet-derived growth factor; RNS: reactive nitrogen species; pSmad: phosphorylated small mothers against decapentaplegic homolog; TGF-β: transforming growth factor-β; TIMP: tissue inhibitor of metalloproteinase; TNF-α: tumor necrosis factor-α; UC: umbilical cord; VEGF: vascular endothelial growth factor).