Management of Fibrosis: The Mesenchymal Stromal Cells Breakthrough

Table 2

MSC treatment on preclinical liver fibrosis models.

References	Organism	Model	Treatment	MSC source	Timing	Quantity	Route	Outcome
[46]	Mouse	CCl4	1 mL/kg twice a week for 8 weeks + 100 𝜇g/kg IL-6 24 and 48 hours after completion of CCl4 treatment	BM	52 hours after CCl4 treatment completion	5 injections of 10^6 cells	Local (liver lobes)	(i) Reduced fibrotic area; (ii) Decreased apoptosis (improved by IL-6 treatment); (iii) Decreased expression of markers of apoptosis (Bax, capsase-3, and NF-κB)
[47]	Mouse	CCl4	0.6 mL/kg twice a week in 1 week	UC	6 weeks after CCl^4 treatment	250 𝜇g of MSC-secreted exosomes		(i) Reduced fibrotic area; (ii) Decreased expression of collagens I and III; (iii) Decreased expression of TGF-β1; (iv) Decreased concentration of TGF-β1 in serum; (v) Decreased phosphorylation of Smad2; (vi) Decreased EMT as evidenced by the decrease in N-cadherin and vimentin positive cells
[48]	Mouse	CCl4	1 mL/kg twice a week for 8 weeks	BM	4 weeks after the beginning of the CCl4 treatment	10^6 cells	Tail vein	(i) Reduced fibrotic area; (ii) Decreased expression of α-SMA; (iii) Decreased expression of collagen type I; (iv) Increased expression of MMP-13
[49]	Mouse	CCl4	1 mL/kg twice a week for 2 or 5 weeks	BM	Immediately following or 1 week after CCl4 treatment	10^6 cells	Tail vein	(i) Reduced fibrotic area; (ii) Decreased expression of TGF-β1 and α-SMA
[50]	Mouse	CCl4	4 weeks CCl4 treatment followed by 4-week SNP treatment	BM	Following CCl4 treatment	10^6 cells	Local	(i) Reduced fibrotic area; (ii) Decreased expression of NF-kB; (iii) Decreased expression of α-SMA; (iv) Decreased expression of collagen 1α1 and TIMP-1; (v) Effect improved by SNP treatment
[51]	Mouse	CCl4	20 mL/kg twice over a 48-hour period	BM		10^6 cells	Tail vein	(i) Reduced fibrotic area; (ii) Decreased expression of α-SMA and collagen 1α1; (iii) Injection of FGF2 partially reproduces the effects of MSCs
[52]	Mouse	CCl4	1 mL/kg twice a week for 8 weeks	AM	After 4 weeks of CCl4 treatment	10^5 cells	Spleen	(i) Reduced fibrotic area; (ii) Increased hepatocyte proliferation; (iii) Increased expression of Bcl-2; (iv) Decreased hepatocyte apoptosis; (v) Reduced number of α-SMA-positive cells; (vi) Increased SOD activity; (vii) Increased expression of HGF and Bcl-2
[53]	Rat	CCl4	5 mL/kg (first injection) followed by 3 mL/kg twice a week for 12 weeks	AT	2 days after CCl4 treatment	2.10^6 cells	Tail vein or hepatic portal vein	(i) Reduced fibrotic area; (ii) Improvement of the microvasculature; (iii) Decreased expression of VEGF
[54]	Rat	CCl4	0.5 mg/kg twice a week for 4 weeks	BM (wild type or HGF-treated)	Following the first CCl4 injection	3.10^6 cells	Tail vein	(i) Reduced fibrotic area (improved effect after MSC pretreatment with HGF); (ii) Decreased inflammation
[55]	Rat	CCl4	0.08 mL/kg twice a week for 6 weeks	BM	Following CCl4 treatment	3.10^6 cells	IV	Decreased collagen concentration
[56]	Rat	CCl4	0.5 mg/kg twice a week for 4 weeks	BM	Following CCl4 treatment	10^6 cells	Hepatic portal vein	Reduced fibrotic area
[57]	Rat	CCl4	1 mL/kg twice a week for 8 weeks	BM (wild type or adipogenic or hepatogenic differentiation)	4 weeks after the beginning of the CCl4 treatment	3.10^7 cells	Spleen injection	(i) Reduced fibrotic area (best outcome with undifferentiated MSCs); (ii) Highest expression of MMP-2 and MMP-9 after undifferentiated MSC transplantation
[58]	Rat	CCl4	1 mL/kg twice a week for 8 weeks	BM (wild type or hepatogenic differentiation)	4 weeks after the beginning of the CCl4 treatment	5.10^6 cells	Tail vein	(i) Decreased fibrotic area (best effect with predifferentiated MSC + baicalin); (ii) Decreased concentration of TNF-α (best effect with predifferentiated MSC + baicalin); (iii) Decreased concentration of TGF-β1 (best effect with predifferentiated MSC + baicalin); (iv) Decreased collagen concentration (best effect with predifferentiated MSC + baicalin)
[59]	Rat	CCl4	0.5 mL/kg (first administration) followed by 1 mL/kg twice a week for 8 weeks (gavage)	UC	4 weeks after the beginning of the CCl4 treatment	5.10^5 cells	Local	(i) Reduced collagen deposition; (ii) Decreased concentration of TGF-β1; (iii) Decreased concentration of α-SMA; (iv) Increased expression of HGF

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; AM: amniotic membrane; AT: adipose tissue; BAX: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; BM: bone marrow; CCl₄: carbon tetrachloride; EMT: epithelial-to-mesenchymal transition; FGF: fibroblast growth factor; HGF: hepatocyte growth factor; IV: intravenous; MMP: matrix metalloproteinase; MSC: mesenchymal stromal cell; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B-cells; SNP: sodium nitroprusside; SOD: superoxide dismutase; 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).