Le Thi Bich et al. Stem Cell Research & Therapy (2020) 11:60 https://doi.org/10.1186/s13287-020-1583-4 RESEARCH Open Access Allogeneic umbilical cord-derived mesenchymal stem cell transplantation for treating chronic obstructive pulmonary disease: a pilot clinical study Phuong Le Thi Bich1, Ha Nguyen Thi1, Hoang Dang Ngo Chau1, Tien Phan Van1, Quyet Do2, Hung Dong Khac2, Dong Le Van2, Luc Nguyen Huy2, Khan Mai Cong2, Thang Ta Ba2, Trung Do Minh2, Ngoc Vu Bich3, Nhat Truong Chau3 and Phuc Van Pham3,4* 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: Umbilical cord-derived mesenchymal stem cells, Mesenchymal stem cells, COPD, Chronic obstructive pulmonary disease * Correspondence: [email protected]; [email protected] 3Stem Cell Institute, VNUHCM University of Science, Ho Chi Minh City, Viet Nam 4Laboratory of Stem Cell Research and Application, VNUHCM University of Science, Ho Chi Minh City, Viet Nam Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Le Thi Bich et al. Stem Cell Research & Therapy (2020) 11:60 Page 2 of 14 Introduction Moreover, MSCs are of interest for therapies using Chronic obstructive pulmonary disease (COPD) was the adult stem cells because they can be used in allogeneic third leading cause of death in the USA in 2005 (https:// transplantation cases that are not HLA-matched be- www.cdc.gov/copd/basics-about.html). According to the tween stem cells and recipients. MSCs express low levels World Health Organization (WHO) estimates, 65 mil- of human leukocyte (HLA) class I [48, 49]. They also do lion people worldwide have moderate-to-severe COPD. not express HLA class II or costimulatory molecules, in- In 2005, more than 3 million people died of COPD, ac- cluding CD40, CD80, and CD86, which are essential for counting for 5% of all deaths that year. Numbers of T cell immune responses [48, 49]. COPD patients are expected to increase by more than MSCs have been applied in both autologous and allo- 30% in the next 10 years (https://www.cdc.gov/copd/ba- geneic transplantations in animals and humans to treat sics-about.html), and COPD is expected to be the third diseases, including COPD. The first allogeneic MSC leading cause of death worldwide in 2020. COPD is transplantation was the application of prochymal to treat treated with medications, including bronchodilators, in- COPD. Prochymal is the first allogeneic off-the-shelf haled steroids, oral steroids, phosphodiesterase-4 inhibi- stem cell treatment produced from human bone mar- tors, theophylline, and antibiotics; lung therapies, such row. This product was approved as a drug in Canada in as oxygen therapy and pulmonary rehabilitation pro- 2012 to treat GVHD. A report from Osiris Therapeutics grams; and surgeries, including lung-volume reduction showed that prochymal transplantation provided some surgery, lung transplantation, and bullectomy. However, benefits without adverse effects in 62 COPD patients but these therapies have limited efficacy and severe adverse did not improve their quality of life or lung function effects [1–3]. Stem cell therapy, especially with mesen- [50]. Other studies have used MSCs derived from bone chymal stem cells (MSCs), is a promising therapy for marrow (BM) or adipose tissue to treat COPD [51–53]; treating various diseases, including inflammation and however, most studies showed limited efficacy [51–53]. autoimmune diseases [4–6]. The failure of these three clinical trials revealed some is- MSCs are adult stem cells often used to treat diseases sues relating to MSC transplantation for COPD. The such as graft-versus-host disease (GVHD) [5], osteoarth- first issue may involve the use of frozen MSCs. In the ritis [7], autoimmune diseases [8], and liver cirrhosis [9]. first clinical trial (NCT00683722), frozen BM-MSCs Several off-the-shelf mesenchymal stem-cell therapies were thawed and directly infused into patients immedi- have been approved as drugs for some diseases. These ately after thawing in frozen bags [50]. The off-the-shelf include Prochymal for GVHD (in Canada) [10], Cartis- BM-MSCs were produced on an industrial scale as tem for knee osteoarthritis (in South Korea) [11, 12], stem-cell drugs. Although this product enables easy and and Temcell HS for GVHD (in Japan) [13]. MSCs can be convenient transplantation, a recent report showed that derived from different sources such as bone marrow newly thawed MSCs lose part of their immunomodula- [14–16], adipose tissue [17–20], peripheral blood [21, tory capacity [54]. Similarly, in the second clinical trial 22], umbilical cord blood [23, 24], and umbilical cord (NCT01306513), the newly thawed cells were also dir- tissue [25–27]. MSCs have three beneficial therapeutic ectly used to treat patients but with low efficacy [51, 52]. mechanisms. First, MSCs can modulate the host im- Thus, fresh cultured BM-MSCs should be used instead mune system by inhibiting some immune cells and of newly thawed BM-MSCs. However, a newer clinical stimulating others [28–30], thus participating in regulat- trial (NCT01110252) used fresh cultured BM-MSCs but ing the immune system. This is the main mechanism of yielded no improvement in clinical outcomes [53]. Thus, the MSCs used to treat GVHD, autoimmune diseases autologous BM-MSCs may be unsuitable for treating and inflammatory diseases [31–36]. Recent studies have COPD. BM-MSCs are usually isolated from adult pa- shown that MSCs can directly interact with immune tients, and BM-MSCs from aging patients can function cells and secrete cytokines or interleukins to regulate abnormally compared with MSCs derived from younger host immune cells [37–40]. The second mechanism re- tissues. In animals, BM-MSCs from aged animals have lates to the MSC secretome. MSCs can produce a wide shorter telomere lengths, reduced differentiation cap- variety of cell signaling cytokines and growth factors tar- acity, impaired proliferation, and decreased paracrine geting endogenous stem cell self-renewal and migration factor production compared with those from younger [41–44] and can trigger host stem cells to self-renew animals [55–57]. In mouse models, BM-MSCs from aged and differentiate to heal an injury. Finally, MSCs can mice showed downregulated cytokine and chemokine re- home and differentiate after transplantation [45–47]. In ceptor expression. These BM-MSCs were also less mobi- some cases, particularly, in autologous transplantation, lized to lung injury compared with BM-MSCs derived MSCs can home and reestablish stem cell niches in the from younger mice [58]. Human BM-MSCs from aged host. These MSCs can differentiate into functional cells patients highly express senescence-related genes, shorter that participate in tissue regeneration. telomere length, low proliferation and low differentiation Le Thi Bich et al. Stem Cell Research & Therapy (2020) 11:60 Page 3 of 14 capacity [59]. In summary, BM-MSCs appear unsuitable (5) Clinical relevance unassociated with COPD during for COPD treatment. screening: left ventricle ejection fraction lower than In contrast to BM-MSCs, umbilical cord-derived 40%, valvular heart disease, cardiomyopathy, MSCs (UC-MSCs) exhibit strong modulation capacity, arrhythmia, congenital heart disease, kidney failure and under the same conditions, we found that UC- with creatinine index > 2.0 mg/dl, liver disease with MSCs more strongly inhibited allogeneic lymphocytes AST, ALT or bilirubin twice the upper limit of the than did BM-MSCs or adipose tissue-derived mesenchy- normal range, hematological disorder, or cancer; mal stem cells [60–62]. UC-MSCs also have higher pro- (6) Using a tumor necrosis factor inhibitor within 3 liferation rates, are more primitive than are BM-MSCs months of the screening visit; [63, 64], and exhibit better potential to differentiate into (7) Using an immunosuppressive medication within 8 other cells [63–66].