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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 67  |  Issue : 1  |  Page : 21-25

Utility of bone marrow mononuclear cells as a novel therapy in chronic obstructive pulmonary diseases


1 Department of Chest, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission02-Oct-2017
Date of Acceptance23-Nov-2017
Date of Web Publication21-Mar-2018

Correspondence Address:
Ibrahim S Ibrahim
Department of Chest, Faculty of Medicine, Tanta University, Tanta, 111134
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejcdt.ejcdt_3_17

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  Abstract 

Background Stem cells have undifferentiated cells that have can proliferate to one or more cells. Exogenous stem cells derived from embryonic and adult tissues could be used in the regeneration of diseased organs, including lung and tissue. Chronic obstructive pulmonary disease (COPD) pathogenesis plays a major role in the upregulation of inflammation, making irreversible procedure, like apoptosis of cells, lysis of the components of extracellular matrix in lung. All treatments of COPD to date have involved pharmacological therapy and mainly target the symptoms; hence, there is an urgent need for novel and more effective therapeutic strategies. Mesenchymal stem cells are considered a therapy in COPD more for their immune modulatory effects.
Aim This study aimed to evaluate the effect of stem cell therapy on mild-to-moderate COPD patients, either by infusion or by inhalation, on the basis of pulmonary function tests and quality of life.
Patients and methods This study was carried out on 30 patients with COPD divided into three groups: 10 patients received COPD medication alone according to the Global Initiative for Chronic Obstructive Lung Disease guidelines (long-acting B2 agonist and inhaled corticosteroids) as a control group, 10 patients received COPD medication plus stem cell infusion, and 10 patients received COPD medication plus stem cell inhalation. Pulmonary functions tests were performed and the quality of life was determined in all patient groups.
Results The pulmonary functions tests showed an insignificant increase in mild-to-moderate COPD patients after 1 month of stem cell, both by infusion and by inhalation, but there was a significant increase in the quality of life with the use of both methods of stem cell treatment compared with the control group.
Conclusion Stem cell therapy leads to significant improvements in the quality of life of patients with mild-to-moderate COPD.

Keywords: chronic obstructive pulmonary disease, MNCs, stem cells therapy


How to cite this article:
Ibrahim IS, Hantera MS, Abdelnaby AY. Utility of bone marrow mononuclear cells as a novel therapy in chronic obstructive pulmonary diseases. Egypt J Chest Dis Tuberc 2018;67:21-5

How to cite this URL:
Ibrahim IS, Hantera MS, Abdelnaby AY. Utility of bone marrow mononuclear cells as a novel therapy in chronic obstructive pulmonary diseases. Egypt J Chest Dis Tuberc [serial online] 2018 [cited 2020 Apr 3];67:21-5. Available from: http://www.ejcdt.eg.net/text.asp?2018/67/1/21/228133


  Introduction Top


Stem cells are undifferentiated cells that proliferate and have the capacity of both self-renewal and differentiation to one or more types of specialized cells [1]. Recent findings suggest that exogenous stem cells derived from embryonic and adult tissues could be used to regenerate injured or diseased organs, including the lung [2]. The tissues which have observed stem or progenitor activity that can be used strongly in cell-based therapies is bone marrow. The bone marrow contains several hematopoietic stem cells, which could be differentiated into many types such as mature blood cells and mesenchymal stem cells (MSCs), which can be differentiated into bone, fat, cartilage, and other mesenchymal tissues [3]. Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease that leads to significant pulmonary and extrapulmonary risks that may contribute toward morbidity in individual patients. This disease is a common cause of mortality and morbidity worldwide [4].

When the epithelium is injured, repair starts immediately. At the edge of the wound, dedifferentiation and migration of the unaffected epithelial cells are initiated immediately to cover the injured area and create several proinflammatory cytokines, causing attraction of proteins and cells needed for restoration of the extracellular matrix, which is essential for wound repair. The human lung consists of different trophic units, each lined by specialized types of airway epithelium. The lung can repair itself when injury is detected by the molecular events that can transfer the stem and progenitor cells toward the trophic units [4].


  Patients and methods Top


This study was carried out on 30 patients with COPD from May 2014 to May 2016. All patients were recruited from the Chest Department, Faculty of Medicine, Tanta University Hospitals. The study was approved by the ethical committee of the faculty of medicine Tanta University.

The participants of the study were divided into three groups:
  • Group I: 10 patients (seven men and three women) serving as a control group received COPD medication alone according to the Global Initiative for Chronic Obstructive Lung Disease guidelines including inhaled corticosteroids and a long-acting B2 agonist.
  • Group II: 10 patients (seven men and three women) received COPD medication plus stem cell infusion.
  • Group III: 10 patients (six men and four women) received COPD medication plus stem cell inhalation.


Written informed consents were signed by all COPD patients before they were recruited into the study. Patients with forced expiratory volume in 1 s (FEV1) less than 50%, chest or heart disease, malignant tumors, pregnant or lactating patients, and patients with a leukocyte count less than 4000/μl, a platelet count less than 100 000/μl, and hemoglobin less than 10 g/dl were excluded from this study.

Patient preparation

Full assessment of history and a thorough clinical examination were performed, along with complete laboratory investigations (complete blood count, blood glucose level, kidney function tests, liver function tests, hepatitis B virus antigens, hepatitis C virus antibodies, and HIV antibodies, arterial blood gases). Abdominal ultrasonography and plain chest radiographs, posteroanterior and lateral views, pulmonary function tests by spirometry, and assessment of quality of life by the clinical chronic obstructive pulmonary disease questionnaire (CCQ) were also performed.

Methodology

Stimulation with granulocyte colony-stimulating factor

All COPD patients received granulocyte colony-stimulating factor (GeneLeukim Injection; China) by a subcutaneous injection for 3–5 successive days before bone marrow aspiration to stimulate the mobilization of stem cells.

Bone marrow aspiration

Bone marrow of 100–120 ml was collected under local or general anesthesia in heparinized tubes using the bone marrow biopsy needle using a completely aseptic technique.

Isolation of human bone marrow mononuclear cells

The bone marrow aspirate was diluted using clinical buffer (cat. no #700–25, Clini MACS PBS/EDTA; Miltenyi Biotec Company, Bergisch Gladbach, Germany) and then filtered by a bone marrow filter (PALL Medical Filter, UK-pore size 100 μm). The filtered cell suspension was layered slowly over Ficoll-Paque (GE Electric, Pharmacia, USA) in a conical tube and centrifuged for 20 min at 20°C at 2000 rpm with brake off. The mononuclear cell layer (monocytes, thrombocytes, and lymphocytes) was transferred to a sterile tube and the cells were washed three times by clinical buffer; then, the pellet of isolated cells was suspended in 500 μl of clinical buffer [5].

Stem cell infusion

The separated bone marrow mononuclear cell pool solution including mobilized stem cells was injected with saline into a peripheral vein using a drip infusion pump.

Stem cell inhalation

The prepared bone marrow mononuclear cell pool solution was inhaled through a nebulizer.

Assessment guidelines

The overall clinical COPD scores of the domains and the control score were calculated by dividing the sum of the scores by the number of questions. Thus, the overall clinical COPD score for each of the three domains as well as the control score vary between 0 (very good) and 6 (extremely poor) (6).

After 6, 12, and 24 months, all patients were followed up for the following:
  1. Pulmonary function tests using spirometry.
  2. Quality-of-life questionnaire using the CCQ.


CCQ is used to determine the symptoms and functional state of patients to quantify the effect of the disease on their daily lives and well-being from the patients’ point of view. It includes three domains (symptoms, function, and mental domain) (9).

CCQ is short (10 items) and easy to complete. It takes patients ∼2 min to complete the questionnaire. Patients are instructed to report their experiences during the last week. They respond to the questions on a scale of 7 points from 0=asymptomatic/no limitation to 6=extremely symptomatic/totally limited domain.


  Results Top


There were no statistically significant differences (P>0.05) between the groups studied in the values of forced vital capacity (FVC) (% of predicted), FEV1% (actual values), the mean values of peak expiratory flow (PEF) (% of predicted), the mean values of maximal mid-expiratory flow (MMEF) (% of predicted), and the mean values of the quality-of-life score ([Figure 1] and [Figure 2]).
Figure 1 Data of the patients in the studied groups before treatment. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MMEF, maximal mid-expiratory flow; PEF, peak expiratory flow.

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Figure 2 Quality of life in the patients of the studied groups before treatment.

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In group I, there were no statistically significant differences (P>0.05) before and after treatment in the mean values of FVC (% of predicted), the mean values of FEV1% (actual values), the mean values of PEF (% of predicted), the mean values of MMEF (% of predicted), and the mean values of the quality-of-life score ([Figure 3] and [Figure 4]).
Figure 3 Spirometry data in group I before and after treatment. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MMEF, maximal mid-expiratory flow; PEF, peak expiratory flow.

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Figure 4 Quality of life in group I before and after treatment.

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In group II, there were no statistically significant differences (P>0.05) before and after treatment in the mean values of FVC (% of predicted), the mean values of FEV1% (actual values), the mean values of PEF (% of predicted), and the mean values of MMEF (% of predicted), whereas there was a significant improvement (P<0.001)in the mean values and SD of quality-of-life score as the scores were 6+1 and 2+1, respectively, before and after treatment ([Figure 5] and [Figure 6]).
Figure 5 Spirometry data in group II before and after treatment. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MMEF, maximal mid-expiratory flow; PEF, peak expiratory flow.

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Figure 6 Quality of life in group II before and after treatment.

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In group III, there were no statistically significant differences before and after treatment in the mean values of FVC (% of predicted), the mean values of FEV1% (actual values), the mean values of PEF (% of predicted), and the mean values of MMEF (% of predicted), whereas there was a significant improvement in the mean values and SD of quality-of-life score as the scores were 6+1 and 1+1, respectively, before and after treatment (P<0.001) ([Figure 7],[Figure 8],[Figure 9]).
Figure 7 Spirometry data in group III before and after treatment. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MMEF, maximal mid-expiratory flow; PEF, peak expiratory flow.

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Figure 8 Quality of life in group III before and after treatment.

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Figure 9 Percent of change in the studied groups after treatment. FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MMEF, maximal mid-expiratory flow; PEF, peak expiratory flow.

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On comparison of the mean values of percent of change of spirometric data in the studied groups before and after treatment, there were no statistically significant differences in FVC (% of predicted), FEV1% (actual values), PEF (% of predicted), and MMEF (% of predicted), whereas the mean values of percent of change of quality-of-life scores in groups I, II, and III after treatment were 2, 4, and 5, respectively. The quality-of-life scores in groups II and III were found to be significantly higher (P<0.001) compared with group I.


  Discussion Top


A significant increase in the quality of life was observed in the present study, which direct the attention of changing the natural process of the disease by inhibiting the progression of the disease and also it was free of significant adverse effects. The results showed an insignificant improvement in the pulmonary functions tests, where FEV1 and FVC showed an insignificant increase in all patients after 24 months of stem cell treatment, both by infusion and by inhalation, and a significant increase in the quality of life in both the groups of COPD patients treated by stem cell infusion or stem cell inhalation compared with the control group.

The National Agency of Sanitary Surveillance stated that the total blood volume that can be aspirated from the bone marrow should not exceed 9 ml/kg for men and 8 ml/kg for women. In our study, we collected between 150 and 200 ml of blood from every patient [6].

Our findings were more or less similar to those of a study carried out in May 2008, which was a double-blinded placebo control phase II trial of allogeneic MSC infusions utilizing PROCHYMALTM for COPD patients with (FEV1/FVC<0.70, 30%≤FEV1≤70%). This study was based on the premise that the anti-inflammatory actions of MSCs will decrease pulmonary inflammation associated with COPD and improve dyspnea, spirometry parameters of the lung, and quality of life [7].

The study of Yanagi et al. [8] reported contrasting findings to ours; they transplanted stem cells in two patients with mucopolysaccharidosis, and associated with obstructive airway disease and obstructive sleep apnea. They found an improvement in the pulmonary function tests, the cornea became clear, which is clouded in mucopolysaccharidosis patients, and the patients’ heart condition improved.

In contrast to our study finding, Yan et al. [8] reported that infusion of bone marrow-derived MSCs at a later stage of lung injury can in fact be deleterious. This leads to the conclusion that an infusion of bone marrow-derived MSCs during an ongoing fibrotic response may augment fibrosis.

From this study, it was concluded that autologous stem cells may potentially be useful for treatment and in the next few years, more research will provide us with major insights into the use of stem and progenitor cells as therapeutic agents in COPD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Mozey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain, cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000; 290:1779.  Back to cited text no. 1
    
2.
Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L et al. Impaired recruitment of bone-marrow derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001; 7:1194–1201.  Back to cited text no. 2
    
3.
Bompais H, Chagraoui J, Canron X, Crison M, Liu XH, Anjo A et al. Human endothelial cells derived from circulating progenitors display specific fuctional properities compared with mature vessel wall endothelial cells. Blood 2004; 103:2577–2584.  Back to cited text no. 3
    
4.
Liu X, Engelhardt JF. The glandular stem/progenitor cell niche in airway development and repair. Proc Am Thorac Soc 2008; 5:682–688.  Back to cited text no. 4
    
5.
Aktas M, Radke TF, Strauer BE, Wernet P, Kogler G. Separation of adult bone marrow mononuclear cells using the automated closed separation system Sepax. Cytotherapy 2008; 10:203–211.  Back to cited text no. 5
    
6.
Stem Cell Pioneers. Stempeutics gets DCGI clearance to start phase II clinical trial for COPD; 2011. Available at: http://www.indiaprwire.com. [Last accessed 2011].  Back to cited text no. 6
    
7.
Osiris Therapeutics Inc. Osiris therapeutis reports interim data for COPD stem cell study; 2010.  Back to cited text no. 7
    
8.
Yanagi S, Kishimoto H, Kawahara K, Sasaki T, Sasaki M, Nishio M et al. Pten controls lung morphogenesis, bronchioalveolar stem cells, and onset of lung adenocarcinomas in mice. J Clin Invest 2007; 117:2929–2940.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]



 

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