Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study

Abstract

Introduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. COPD results from chronic inflammation of the lungs. Current treatments, including physical and chemical therapies, provide limited results. Stem cells, particularly mesenchymal stem cells (MSCs), are used to treat COPD. Here, we evaluated the safety and efficacy of umbilical cord-derived (UC)-MSCs for treating COPD.

Methods: Twenty patients were enrolled, 9 at stage C and 11 at stage D per the Global Initiative for Obstructive Lung Disease (GOLD) classification. Patients were infused with 10⁶ cells/kg of expanded allogeneic UC-MSCs. All patients were followed for 6 months after the first infusion. The treatment end-point included a comprehensive safety evaluation, pulmonary function testing (PFT), and quality-of-life indicators including questionnaires, the 6-min walk test (6MWT), and systemic inflammation assessments. All patients completed the full infusion and 6-month follow-up.

Results: No infusion-related toxicities, deaths, or severe adverse events occurred that were deemed related to UC-MSC administration. The UC-MSC-transplanted patients showed a significantly reduced Modified Medical Research Council score, COPD assessment test, and number of exacerbations. However, the forced expiratory volume in 1 s, C-reactive protein, and 6MWT values were nonsignificantly reduced after treatment (1, 3, and 6 months) compared with those before the treatment.

Conclusion: Systemic UC-MSC administration appears to be safe in patients with moderate-to-severe COPD, can significantly improve their quality of life, and provides a basis for subsequent cell therapy investigations.

Trial registration: ISRCTN, ISRCTN70443938. Registered 06 July 2019.

Keywords: COPD; Chronic obstructive pulmonary disease; Mesenchymal stem cells; Umbilical cord-derived mesenchymal stem cells.

Fig. 1

Flow chart of the study population selection including patient recruitment, exclusion criteria, and refusals

Fig. 2

Work-flow of UC-MSC production for clinical application. Donors were screened to select suitable donors for umbilical cord collection. Umbilical cord tissue was used to isolate UC-MSCs by primary culture; them UC-MSCs were expanded before they were freezed. During the process, UC-MSCs were checked to control the UC-MSC quality

Fig. 3

UC-MSC culture and expansion. The MSCs migrated from the tissue after 7 days of primary culture (a). They were subcultured for UC-MSC mater banks (b). The UC-MSCs were thawed and cultured for transplantation (c)

Fig. 4

UC-MSCs expressed the common markers of MSCs suggested by ISCT. They expressed CD44, CD73, CD90, and CD105; and did not express CD14, CD34, CD45, and HLA-DR

Fig. 5

UC-MSCs were successfully differentiated into adipocytes, osteoblasts, and chondroblasts. After differentiation, UC-MSCs successfully differentiated into adipocytes (a) that were positive with Oil Red staining (b); into osteoblasts that positive with Alizarin red staining (c); into chondroblasts that positive with Alcian blue staining (d)

Fig. 6

UC-MSCs can inhibit T cell proliferation after 3 and 5 days co-culture. After 3 days of co-culture with PBMC, UC-MSCs can efficiently PHA-treated PBMC proliferation. After 5 days of co-culture, UC-MSCs can strongly inhibit the both PHA-treated PBMC and non-treated PBMC proliferation

Fig. 7

Clinical outcomes before treatment and during follow-up period by GOLD stages (C and D stages)