Table 2.
Studies testing the therapeutic effect of stem/progenitor cells in experimental adult lung disease models
| Experimental Model | Therapeutic Cell of Product | Outcomes | Suggested Mechanisms | References |
|---|---|---|---|---|
| Bleomycin Lung Injury/Acute Respiratory Distress Syndrome | ||||
| Bleomycin-induced (i.t.) | Human ESC-derived cells with AT2 epithelial phenotype (i.t.) | Improved body weight and survival Improved arterial oxygen saturation Decreased collagen deposition |
Engraftment and AT1 differentiation Paracrine mechanisms |
79 |
| Bone marrow–derived MSCs (i.v.) | Reduced fibrosis and inflammation | IL-1 receptor antagonism Decrease in NO metabolites, proinflammatory, and angiogenic cytokines |
44, 80, 81 | |
| hUC Wharton jelly–derived MSCs (i.v.) | Reduced fibrosis | Decreased TGF-β and TIMP activity Increased MMP-2 activity |
82 | |
| Bone marrow–derived HSCs ± KGF overexpression (i.v.) | Reduced fibrosis | KGF-induced endogenous AT2 cell proliferation | 83 | |
| Bleomycin-induced (i.n.) | hAECs (i.p.) | Reduced fibrosis and collagen deposition Improved lung function Modulated inflammatory response |
Anti-inflammatory effects | 84 |
| Escherichia coli endotoxin-induced (i.p.) | Bone marrow–derived MSCs (i.v.; i.t.) | Improved survival Decreased systemic and local inflammation |
Cell-cell interactions Paracrine mechanisms Decreased proinflammatory and increased anti-inflammatory cytokines Antioxidant mechanisms |
85, 86, 87 |
| E coli endotoxin-induced (i.t.) | iPS cells and CdM (i.v.) | Attenuated lung injury Reduced inflammation Reduced MPO and NF-κB activity Improved Pao2 and lung function |
Paracrine mechanisms Regulation of neutrophil activity Attenuating inflammatory cascade Immunomodulatory effects |
88 |
| Bone marrow–derived MSCs overexpressing Ang-1 (i.v.; i.t.) | Decreased inflammation Decreased alveolar permeability |
Decreased inflammatory cytokines Ang-1–mediated effects |
89, 90 | |
| hUCB-derived MSCs (i.t.) | Increased survival Attenuated lung injury Reduced inflammation Increased MPO activity Inhibited bacterial growth |
Down-modulating inflammatory process Enhancing bacterial clearance |
91 | |
| LPS-induced (i.t.) | Human orbital fat–derived stem/stromal cells (i.v.) | Decreased systemic and local inflammation Decreased alveolar and endothelial permeability |
Inhibition of macrophage and neutrophil-associated inflammatory responses | 92 |
| EPCs (i.v.) | Improved Pao2 and SaO2 Preservation of alveolocapillary permeability Reduced interstitial edema, hyaline membrane formation, hemorrhage |
Paracrine mechanisms Anti-inflammatory effects |
93 | |
| hUCB-derived MSCs (i.t.) | Increased survival Reduced edema, hemorrhage, alveolar and endothelial permeability Reduced inflammation |
Paracrine mechanisms Anti-inflammatory effects |
94 | |
| LPS-induced (i.v.) | EPCs (i.v.) | Reduced pulmonary edema, inflammation, hemorrhage, and hyaline membrane formation Decreased adhesion molecule expression Reduced endothelial and epithelial cell apoptosis |
Engraftment of EPCs Re-endothelialization Downregulation of adhesion molecules Alleviation of inflammatory response Apoptosis prevention |
95 |
| Ventilator-induced | Bone marrow–derived MSCs and CdM (i.v.) | Improved lung function Modulated inflammation Restored lung structure |
Paracrine mechanisms | 96 |
| Pulmonary Hypertension | ||||
| Monocrotaline-induced | Bone marrow–derived MSCs ± eNOS overexpression (i.v.; i.t.) | Improved survival Improved RV pressure overload and function Improved lung structure |
eNOS-mediated vasodilation VEGF-mediated enhanced microvasculature Paracrine effects |
97, 98, 99, 100 |
| Bone marrow–derived EPCs (i.v.) | Restored pulmonary hemodynamics Increased microvascular perfusion |
eNOS-mediated vascular growth | 101 | |
| Peripheral blood-derived EPCs (i.t.) | Improved cardiac function Improved vasculature thickness and lung neovascularization |
102 | ||
| Asthma/Allergic Airway Inflammation | ||||
| Ovalbumin-induced (i.p. and i.t.; nebulized) | Adipose tissue–derived MSCs (i.v.) | Decreased local and systemic allergic response | Decreased Th2 activity | 103, 104 |
| Bone marrow–derived MSCs (i.v.) | Reduced airway hyperresponsiveness and remodeling Reduced serum NO levels Reduced inflammatory cell infiltration and mast cell degranulation |
Immunomodulatory effects Anti-inflammatory effects |
105, 106 | |
| BMC-CdM | Prevented airway inflammation Reduced airway remodeling Prevented airway hyperresponsiveness |
Paracrine mechanisms Anti-inflammatory effects of adipokine, APN |
107 | |
| Ragweed-induced (i.p.) | Bone marrow–derived MSCs (i.v.) | Decreased asthma-specific allergic response | TGF-β production Regulatory T-cell recruitment |
108 |
| Chronic Obstructive Pulmonary Disease/Emphysema | ||||
| Cigarette smoke–induced | Bone marrow–derived MSCs, CdM, and BMCs (i.v.) | Restoration of alveolar structure Increased pulmonary vascularity Alleviation of pulmonary hypertension (by BMCs) |
Paracrine mechanisms Recruitment of BMCs by donor cells |
109 |
| Papain-induced | Bone marrow–derived MSCs (i.v.) | Improved alveolar structure | Engraftment and AT2 differentiation Reduced alveolar epithelial apoptosis |
110 |
| Elastase-induced (i.t.) | Adipose tissue–derived MSCs (i.v. or cultured on PGA and transplanted after LVRS) | Restored gas exchange Improved exercise tolerance |
Growth factor release (HGF, VEGF) | 111, 112 |
| Bone marrow–derived MSCs (i.t.) | Preservation of alveolar structure Reduced inflammation Upregulated growth factors |
Paracrine mechanisms HGF, EGF, and secretory leukocyte protease inhibitor secretion |
113 | |
| Lung resident multilineage progenitors Sca1+CD45−CD31− (i.t.) | Improved survival Attenuated alveolar damage |
Immunomodulatory effects Paracrine mechanisms |
114 | |
Abbreviations: Ang-1, angiopoietin-1; APN, adiponectin; AT1, alveolar epithelial type 1; AT2, alveolar epithelial type 2; BMC, bone marrow–derived cells; CdM, conditioned media; EGF, epidermal growth factor; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; HGF, hepatocyte growth factor; HSC, hematopoietic stem cell; hAEC, human amnion epithelial cell; hUC, human umbilical cord; hUCB, human umbilical cord blood; IL, interleukin; i.n., intranasal; i.p., intraperitoneal; iPS, induced pluripotent stem; i.t., intratracheal; i.v., intravenous; KGF, keratinocyte growth factor; LPS, lipopolysaccharide; LVRS, lung volume reduction surgery; MMP-2, matrix metalloproteinase 2; MPO, myeloperoxidase; MSC, mesenchymal stem cell; NF-κB, nuclear factor kappa light-chain enhancer of activated B cells; NO, nitric oxide; Pao2, partial pressure of oxygen in arterial blood; PGA, polyglycolic acid; RV, right ventricle; Sao2, oxygen saturation; TGF-β, transforming growth factor β; Th2, helper T cell type 2; TIMP, tissue inhibitor of metalloproteinase; VEGF, vascular endothelial growth factor.