Table 6.

Summary of selected preclinical studies in rodents aiming to improve the therapeutic efficacy of MSC by genetic modification.

Disease Entity	Experimental Lung Disease Model	Cell Source	MSC Modification	MSC Species	Dose (Cells)	Application Route	Time Point of Application	Repeated Application	Biological Function In Vivo	Molecular Changes/Results	Reference
ALI	LPS	BM	FGF2 overexpression	mice	5 × 106	i.v.	1 h p.i.	no	FGF2 overexpression better preserves lung structure and pulmonary edema	MSC overexpressing FGF2 better attenuate pro-inflammatory cytokine and MPO secretion and neutrophil infiltration	[153]
ALI	LPS	BM	CXCR4 overexpression	rat	1 × 106	i.v.	1 h p.i.	no	reduced lung injury score and lung edema	enhanced mobilization and chemotaxis of MSC, increased VEGFA secretion and reduced lung inflammation	[154]
ALI	LPS	BM	β-catenin overexpression	mice	5 × 105	i.t.	4 h p.i.	no	improvements in alveolar epithelial barrier integrity and lung structure impairment	better MSC retention in the lung and AEC II transdifferentiation with higher levels of KGF and IL-10 and reduced IL-1β	[155]
ALI	LPS	BM	siRNA against claudin-4	human	1 × 106	i.p.	n.a.	no	Claudin-4 promotes alveolar fluid clearance	hypoxic MSC preconditioning stipulates claudin-4 secretion	[28]
ALI	LPS	BM	MSC transfected with shRNA against VEGFA	rat	5 × 106	i.v.	5 h p.i.	no	attenuated anti-inflammatory properties and beneficial effects on lung injury	transfected MSC reduced the proinflammatory cytokine IL-1β levels and elevated the anti-inflammatory cytokine IL-10 levels	[151]
ALI	LPS	BM	shRNA HGF transfection	rat	5 × 106	i.v.	5 h p.i.	no	partial abrogation of MSC effects, MSC retention in the lung was not influenced, MSC restores lung permeability and lung injury	HGF-expressing character is required for MSC to protect the injured lung	[148]
ALI	LPS	AM	Nrf2 transfected MSC	human	1 × 106	i.v.	4 h p.i.	no	reduced inflammation, epithelial cell injury and fibrosis	increased cell retention in the lung, more efficient differentiation into type II cells with higher SPC content	[162]
ALI	E. coli	UCB	IL-10 transgentic MSC	human	1 × 107/kg	i.v.	1 h p.i.	no	increased therapeutic efficiency of transgenic MSC which only prohibited all aspects of lung injury including gas exchange	enhanced macrophage function via prostaglandin E2 and lipoxygenase A4	[158]
ALI	LPS	BM	transduction with heme oxygenase-1	rat	5 × 105	i.v.	2 h p.i.	no	improved survival rates, reduced lung inflammation and structural changes	superior prosurvival, antiapoptotic and paracrine functions	[150]
BPD	hyperoxia	BM	shRNA stromal cell-derived factor-1	rat	1 × 106	i.t.	d7	no	reduction of beneficial MSC effects on alveolarization and angiogenesis	SDF-1 from MSC exerts anti-inflammatory and angiogenesis promoting activities	[159]
asthma	ovalbumin	BM	erythropoietin gene modified MSC	mice	n.a.	i.v.	d20	no	more efficient inhibition of all disease driving pathologies	maybe related with the downregulation of TGF-β1-TAK1-p38MAPK pathway activity	[173]
COPD	elastase	BM	VEGFA overexpression	mice	n.a.	i.v.	14 d a.t.	no	Improved attenuation of emphysema compared to naïve MSC	Increased tissue expression of VEGFA, Nrf 2 and superoxide dismutase	[84]
COPD	elastase	BM	shRNA HGF knockdown	human	0,1 vs. 5 vs. 25 vs. 125 × 103/g	i.v.	6 h vs. d7 vs. d14 a.t.	no	MSC cell therapy more efficient than conditioned medium, higher doses and mid to delayed application better reduces collagen deposition and anti-inflammatory effects	anti-inflammatory, antifibrotic and antiapoptotic effects mediated partially through HGF	[187]

i.v.—intravenous; i.t.—intratracheal; i.p.—intraperitoneal; p.i.—post infection; a.t.—after treatment; MSC—mesenchymal stem cell; ALI—acute lung injury; BPD—bronchopulmonary dysplasia; COPD—chronic obstructive pulmonary disease; UCB—umbilical cord blood-derived MSC; BM—bone marrow -derived MSC; AM—amniotic-derived MSC; h – hours; d—day; n.a.—not applicable; FGF2—fibroblast growth factor 2; MPO—myeloperoxidase; VEGFA—vascular endothelial growth factor A; AEC II—alveolar epithelial cells type II; KGF—keratinocyte growth factor; IL—interleukin; HGF—hepatocyte growth factor; SDF-1—stromal cell-derived factor 1; TGF-ß—transforming growth factor beta; TAK1—transforming growth factor beta-activated kinase 1; p38MAPK—P38 mitogen-activated protein kinase; NRF 2—Nuclear factor erythroid 2-related factor 2.