Management of Fibrosis: The Mesenchymal Stromal Cells Breakthrough

Table 1

MSC treatment on preclinical heart fibrosis models.

References	Organism	Model	Treatment	MSC source	Timing	Quantity	Route	Outcome
[41]	Pig	Ligation	Ligation of the left coronary artery for 90 minutes before reperfusion	BM	30 minutes after reperfusion	3.10^7 cells + atorvastatin	Infarction and peri-infarction zone	(i) Reduced fibrotic area; (ii) Reduced inflammation score; (iii) Decreased apoptosis; (iv) Increased cNOS activity; (v) Atorvastatin increases MSC survival
[42]	Rat	DOX	2.5 mg/kg 6 times in 2 weeks	BM	1 week after the first DOX injection	−5.10^6 cells or −1 mL of MSC-conditioned medium	Tail vein	(i) Reduced fibrotic area (similar effect with MSC-conditioned medium); (ii) Increased Bcl-2/Bax ratio (similar effect with MSC-conditioned medium); (iii) High concentration of HGF and IGF-1 in MSC-conditioned medium
[43]	Rat	ISO	170 mg/kg every day for 4 days	BM	4 weeks after the final ISO injection	3.10^6 cells	Intramyocardial	(i) Reduced fibrotic area.; (ii) Decreased expression of type I collagen; (iii) Decreased expression of pro-MMP-2, active MMP-2, and MMP-9; (iv) Decreased concentration of MMP-2 and MMP-9; (v) Increased concentration of HGF; (vi) Increased expression of HGF (sham level)
[44]	Rat	Ligation	Ligation of the interventricular artery	BM (wild type or melatonin treated)	2 weeks after ligation	3 injections of 2.10^6 cells or 3 injections of 50 𝜇L of MSC-conditioned medium	Intramyocardial	(i) Reduced fibrotic area (improved effect with melatonin); (ii) Stimulation of angiogenesis; (iii) Increased concentration of HGF (improved effect with melatonin)
[45]	Rat	Ligation	Ligation of the left coronary artery	FM or BM	4 weeks after ligation	Two-layered MSC sheets	Anterior heart wall	(i) Reduced fibrotic area; (ii) Increased proportion of M2 macrophages; (iii) Increased concentration of VEGF; (iv) Increased capillary density in peri-infarct area; (v) Some MSCs engrafted 28 days after transplantation; (vi) Some engrafted MSCs express α-SMA and/or lectin-I; (vii) No significant difference between FM and BM-MSCs

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; BAX: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; BM: bone marrow; DOX: doxorubicin; FM: fetal membrane; HGF: hepatocyte growth factor; IGF: insulin-like growth factor; ISO: isoproterenol; MMP: matrix metalloproteinase; MSC: mesenchymal stromal cell; NOS: nitric oxide synthase; VEGF: vascular endothelial growth factor).