Role of Stem Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Pulmonary Emphysema

Figures & data

Figure 1. The epithelial stem cells in the human lung.

Table 1. Published clinical trials of stem cell therapies in patients with COPD and/or pulmonary emphysema.

Study (ref)	Ribeiro-Paes (157)	Stessuk (158)	Weiss (151)	Stolk (152)	De Oliveira (159)	Comella (160)
Site of the study	Brazil	Brazil	USA (6 states)	Netherlands	Brazil	Mexico
Clinical trials Registry code	NCT01110252	NCT01110252	NCT00683722	NCT01306513	NCT01872624	Not found
Design	Single centre, non-randomised, open-label	Phase I, follow up to 3 years of previous study	Phase II, Multicentre, Randomised, Double-blind, Placebo-controlled	Phase I, prospective open-label	Phase I, prospective, non-randomised, patient blinded, placebo-controlled	Phase I, non-randomised, open label
Disease and patients (n)	Severe COPD (n = 4)	Severe COPD (n = 4)	Moderate to Severe COPD (n = 62); FEV1 post-BD >30%, <70%	Severe pulmonary emphysema (n = 10), mean FEV1 32% of predicted	Severe pulmonary emphysema (n = 10), FEV1< 45%	Severe COPD (n = 12)
Cell type	Autologous BM-MSC	Autologous BM-MSC	Allogenic BM-MSC (Prochymal)	Autologous BM-MSC	Allogenic BM-MSC	Autologous stromal vascular fraction (ADMSC)
Delivery route	IV	IV	IV	IV	Intrabronchial (before the implantation of valve endobronchial)	IV
Primary outcomes	Safety, lung function (FEV1, FVC, VC)	Lung function (FEV1, FVC, VC)	Safety in 2 years follow up	Safety and feasibility in patients undergoing to lung volume reduction surgery	Absence of lung deficits during the procedure and/or in the 4 months follow-up	Immediate and long-term safety (12 months)
Secondary outcomes	Arterial blood gases test (PaO2 and PaCO2)		Lung function, 6MWT, Borg scale, SGRQ, time to first exacerbation	FEV1	SGRQ, lung function, serum CRP, BODE index	SGRQ
Safety results	Absence of significant adverse effects	Absence of significant adverse effect	Mild to moderate adverse events in MSC-group 57%, in placebo-group 66%; severe adverse events in MSC-group 23%, in placebo-group 16%	Absence of significant adverse effects	No patient in MSC group experienced adverse events	Absence of adverse effects

Table 2. Results of stem cell therapies in patients with COPD and/or pulmonary emphysema.

	Ribeiro-Paes (157)	Stessuk (158)	Weiss (151)	Stolk (152)	De Oliveira 159	Comella 160
Results (p values and changes)	There is no significant improvement of lung function and of arterial blood gases at 90 d	One patient died 12 months after the procedure. The FEV1 remained stable during follow up for 3 years	No statistically significant difference between two groups in FEV1, FVC, TLC, DLCO, 6MWT, SGRQ, Borg scale, number of exacerbations in 2-years-follow up. In the patients with elevated serum CRP at baseline (>4 mg/L) the CRP levels decreased at 1 month in MSC group (p<.05)	At 12-months theFEV1 increase of 390 ml at average compared to the baseline (p = 0.03), RV decreased of 540 mL (p=.053), body weight increased of average 4.6 Kg (p=.016), and lung CD31+ cells increased (p=.016)	Serum CRP level was reduced in MSC group (p<.05) at days 30 and 90. The BODE index decreased from 8 at baseline to 3 at 90 d in MSC group (p<.05); The dimensionless unit of SGRQ decreased from 68 to 30 at 90 d in MSC group (p<.05). No significant differences in FEV1, FVC, TLC, PaO2, PaCO2, DLCO, BMI, and 6MWD	SGRQ score was decreased from 73 units at baseline to 45 units at 3 months (p=.005) and to 44 units at 6 months (p=.008)

Table 3. Minimal clinically important difference (MCID).

Parameter	Explanation	MCID
FEV1	Airflow obstruction	100–140 mL
CAT	COPD assessment test for the impact of COPD on person’s life (8 items, each score from 0 to 5 [worst])	Improvement of 2 or more units.
TDI	Transition Dyspnoea Index 24-item survey that measures the impact of shortness of breath on functional impairment, magnitude of task and magnitude of effort. Total scores range from −9 (worst) to +9 (best)	Improvement of 1 or more units.
SGRQ	St. George’s Respiratory Questionnaire measures the health status and quality of life: 50-item survey asking about symptoms, activity, and social or psychological impact. Total scores range from 0 (best) to 100 (worst)	Reduction of 4 or more units.
COPD exacerbations	Measured by exacerbation rate or time to exacerbation rate	No validated MCID. Suggested MCID =1 less exacerbation a year for an individual patient, or a 15–20% reduction in overall exacerbation rate compared with placebo (exacerbation rate ≥20% reduction in a patient having 1/year: NNTB ≤5)

Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Marcelino MY, Stessuk T, de Faria CA, Lago MR. Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis. 2011;6:63–71. doi:10.2147/COPD.S15292.

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Stolk J, Broekman W, Mauad T, Zwaginga JJ, Roelofs H, Fibbe WE, Oostendorp J, Bajema I, Versteegh MI, Taube C, et al. A phase I study for intravenous autologous mesenchymal stromal cell administration to patients with severe emphysema. QJM. 2016;109(5):331–336. doi:10.1093/qjmed/hcw001.

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De Oliveira HG, Cruz FF, Antunes MA, de Macedo Neto AV, Oliveira GA, Svartman FM, Borgonovo T, Rebelatto CL, Weiss DJ, Brofman PR et al. Combined bone marrow-derived mesenchymal stromal cell therapy and one-way endobronchial valve placement in patients with pulmonary emphysema: a phase I clinical trial. Stem Cells Transl Med. 2017;6:962–969. doi:10.1002/sctm.16-0315.

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Comella K, Blas JAP, Ichim T, Lopez J, Limon J, Moreno RC. Autologous stromal vascular fraction in the intravenous treatment of end-stage chronic obstructive pulmonary disease: a phase I trial of safety and tolerability. J Clin Med Res. 2017;9(8):701–708. doi:10.14740/jocmr3072w.

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