Animal models investigating MSCs in COPD: methods and main outcomes
| Author (year) | Model | Cell source, number, route | Timing/frequency of cell therapy (from start) | Assessment of effects (from last cell therapy) | Main findings |
| Antunes et al 61 (2014) | C57BL/6 mice IT PPE weekly 4 weeks | AT-MSC, BM-MSC and LR-MSC 0.1×106 intravenous and intratracheal | Week 4 Once | 7 days | All sources improved MLI, reduced inflammation and apoptosis. AT-MSC and BM-MSC improved mPAP and increased VEGF. Change of macrophages from M1 to M2 profile in BM-MSC group. |
| Gu, et al 34 (2015) | SD-rat CS exposure 12 weeks | BM-MSC 6×106 IT | Week 8–12, twice-weekly 10 times | 28 days | Improved MLI and reduced inflammation (including increased M2 macrophages in BALF) through downregulation of COX2 and PGE2, possibly via alveolar macrophages. |
| Guan, et al 50 (2013) | SD-rat CS exposure 11 weeks | BM-MSC 6×106 IT | Week 7 Once | 9 weeks | Improved MLI and PFT, reduction of pro-inflammatory mediators and proteases, reduced apoptosis. Increased VEGF, VEGFR and TGF-β. |
| Hoffman, et al 74 (2011) | C57BL6/J mice IT PPE once | BM-MSC and LR-MSC 0.5 and 1.0×106 IV (1), 0.33×106 IV (2) | Week 6 or 7, once (1) Twice-weekly, thrice (2) | 22 (1) or 28 (2) days | Both sources improved MLI and increased IL-6 levels. No evidence of transdifferentiation. LR-MSC showed higher survival and retention in the lung compared with BM-MSCs. |
| Huh, et al 45 (2011) | Lewis rat CS exposure 6 months | BMC/BM-MSC 0.6×106/6 x106 RB or MSC-CM | Month 6 Once | 1, 7, 14, 28 days (BMC) and 8 weeks | Improved MLI and vascular parameters (mPAP, numbers of small pulmonary vessels), increased proliferation and reduced apoptosis. Paracrine effect rather than engraftment. |
| Ingenito, et al 53 (2012) | Sheep EB PPE monthly 5 months | Autol. LR-MSC 5–10×106 EB on scaffold | Week 8 Once | 28 days | Increased tissue mass on CT with increased lung perfusion and ECM content. Only a fraction of LR-MSCs appeared to engraft. Proposed mechanism: promoted outgrowth of epithelial and endothelial cells through secretion of ECM components. |
| Katsha, et al 32 (2011) | C57BL/6 mice IT PPE once | BM-MSC 0.5×106 IT | Day 14 Once | 7, 14 and 21 days | Improved MLI, increased levels of HGF, EGF and SLPI. Proposed mechanism via paracrine factors; infrequent engraftment or differentiation into epithelial cells. |
| Kennelly, et al52 (2016) | NOD/SCID/IL-2Rγnull mice IN PPE 6 times 2 weeks | BM-MSC (human) 0.5×106 IV or MSC-CM | Day 0 (1), 7 (2) or 12 (3) or day 0 (CM) Once | 14 (1), 7 (2) or 16 (3) days or 14 days (CM) | Dose-dependent, protective effects of MSCs: decreased inflammation, less apoptosis and fibrosis. CM is protective but less effective. Proposed mechanism via HGF secretion. |
| Khedoe, et al 71 (2017) | APOE*3-Leiden mice IN LPS 2x/w 20 weeks | BM-MSC 0.5×106 IV | Week 14, 16, 18, 20 4 times | 7 days | No effect on lung function parameters, MLI, lung tissue remodelling, pulmonary inflammatory infiltrates or cytokine levels in BAL or plasma. |
| Kim, et al 62 (2015) | C57BL/6J mice IT PPE once | UC-MSC (human) 0.01–0.1×106 IV | Day 7 Once | 7 days | Dose finding: improved MLI and increased VEGF with 0.05×106 MSCs. No effects on apoptosis, MMPs, SLPI, TIMP1, HFG and FGF2. |
| Li, et al 54 (2014) | SD-rat CS exposure 56 days | BM-MSC and iPSC-MSC (human) 3×106 IV | Day 29 and 43 Twice | 14 days | Both sources improved MLI, but iPSC-MSCs were more effective which is ascribed to higher mitochondrial transfer capacity of iPSC-MSCs. |
| Li, et al 65 (2014) | SD-rat CS exposure+LPS twice 12 weeks | AF-MSC 4×106 IT | Week 12 Once | 20 and 40 days | Improved MLI, less apoptosis of AT2 cells, increased expression of SPA, SPC and TTF1. Proposed mechanism: integration into lung tissue and differentiation into AT2-like cells. |
| Liu, et al 66 (2015) | C57/B6 mice CS exposure 12 weeks | BM-MSC 4×106 IV | Week 5–12, once-weekly 8 times | 14 days | Improved MLI, decreased apoptosis and inflammation, increased proliferation. No effects on PFT. Significant increase in numbers of BASCs. |
| Peron, et al 63 (2015) | C57BL/6 mice CS exposure 75 days +/-laser | T-MSC (human) 1×106 intranasal or intraperitoneal | Day 60 and 67 Twice | 9 days | Laser-irradiated MSCs resulted in less inflammation, mucus production, collagen accumulation and tissue damage. Proposed mechanism: reduced NF-κB and NF-AT activation and increased IL-10. |
| Schweitzer, et al 49 (2011) | DBA/2J and C57BL/6 mice CS exposure 2 (1), 24 weeks (2) or VEGFR-inh (3) | AT-MSC (human) 0.3×106 IV | Day 14 once (1), month 2–4 twice-weekly, 4 times (2) or day 3 once (3) | 1, 7, 21 days (1); 1 day (2) or 3 and 25 days (3) | Reduced inflammatory infiltration, decreased lung cell death and airspace enlargement. Effects on bone marrow and weight loss. |
| Shigemura, et al 60 (2006) | Lewis rat IT PPE once | AT-MSC 50×106 IV | Day 7 Once | 7, 14, 21 and 28 days | Increased HGF. Inhibition of alveolar cell apoptosis, enhancement of epithelial cell proliferation and promotion of angiogenesis. Restored PFT. |
| Song, et al 69 (2014) | SD-rat CS exposure 7 weeks | BM-MSC 6×106 IT | Week 8 Once | 28 days | Less pro-inflammatory cytokines and inflammatory cells in BALF, improved histopathology and airflow obstruction. Proposed mechanism via induction of TGF-β1. |
| Tibboel, et al64 (2014) | C57/BL6 mice IT PPE once | BM-MSC 0.5×106 IT (1) or 0.1×106 IV (2) | 1 day prior, day 1 or day 21 (1); 30 min prior (2) once | 19, 20 and 21 days | MSCs IV inhibited deterioration of lung function, without effects on histology. IT administration of MSCs had no effects. |
| Zhang, et al 72 (2014) | SD-rat CS exposure+IT LPS twice 8 weeks ±SPA (d 61) ±irr (d 90) | BM-MSC 4×106 IV | Day 90 Once | 31 days | Following SPA suicide gene system infusion: increased recruitment of MSCs with induction of pulmonary fibrosis, proposed mechanism: due to vacant AT2 cell niches. Decreased IL-6 in BALF. |
| Zhen et al 67 (2008) | Lewis rat IT papain once +/-irr | BM-MSC 4×106 IV | Day 0 Once | 28 days | Amelioration of emphysematous changes. MSC engraftment in recipient lungs and differentiation into AT2 cells. Suppression of alveolar cell apoptosis. |
| Zhen et al 51 (2010) | Lewis rat IT papain once | BM-MSC 4×106 IV | Day 0 (2 hours) Once | 28 days | Improved MLI, restoration of reduced VEGFA expression. |
AF, amniotic fluid; AT-MSC, adipose tissue-derived stromal cell; AT2, alveolar type 2 cell; Autol., autologous; BALF, bronchoalveolar lavage fluid; BASCs, bronchoalveolar stem cells; BM, bone marrow; BMC, bone marrow cells; COX2, cyclooxygenase 2; CS, cigarette smoke; EB, endobronchial; ECM, extracellular matrix; EGF, epidermal growth factor; HGF, hepatocyte growth factor; IL, interleukin; inh, inhibition; iPSC, induced pluripotent stem cell; irr, irradiation; LPS, lipopolysaccharide; LR, lung resident (lung-derived); MLI, mean linear intercept; MMPs, matrix metalloproteases; mPAP, mean pulmonary artery pressure; MSC, mesenchymal stromal cell; MSC-CM, MSC conditioned medium; NF-AT, nuclear factor of activated T-cells; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOD/SCID/IL-2Rγnull, non-obese diabetic/severe combined immunodeficiency IL-2 receptor gamma knockout; PFT, pulmonary function test; PGE2, prostaglandin E2; PPE, porcine pancreatic elastase; RB, retrobulbar; SD, Sprague Dawley; SLPI, secretory leucocyte protease inhibitor; SPA, surfactant protein A; SPC, surfactant protein C; T, tubal derived; TGF-β, transforming growth factor-β; TIMP, tissue inhibitor of metalloproteinases; TTF1, thyroid transcription factor 1; UC, umbilical cord; VEGFR, vascular endothelial growth factor receptor.