MINISTRY OF EDUCATION AND TRAINING MINISTRY OF HEATH HANOI MEDICAL UNIVERSITY ====== VU THI THU TRANG APPLICATION OF AUTOLOGOUS BONE MARROW STEM CELLS THERAPY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE MANAGEMENT Specialism : Pulmonary Medicine Code : 9720107 ABSTRACT OF THESIS HA NOI – 2023 The thesis has been completed at HANOI MEDICAL UNIVERSITY Supervisors: A. Phan Thu Phuong. Nguyen Huy Luc. Bach Khanh Hoa.
Nguyen Viet Nhung. PhD The thesis will be present in front of board of university examiner and reviewer lever at…. 2023 This thesis can be found at: National Library National Medical Informatics Library Library of Hanoi Medical University THE LIST OF WORKS HAS PUBLISHED AND RELATED TO THE THESIS 1. Ngô Quý Châu, Phan Thu Phương, Nguyễn Tuấn Tùng, Vũ Văn Trường, Vũ Thị Thu Trang*, Nguyễn Thanh Thủy, Đào Ngọc Phú, Đặng Thành Đô, Nguyễn Đức Nghĩa (2019).
“Kết quả bước đầu ghép tế bào gốc tự thân từ tuỷ xương điều trị bệnh phổi tắc nghẽn mạn tính tại Trung tâm Hô hấp, Bệnh viện Bạch Mai”. Tạp chí Y học Việt Nam, tập 477 số đặc biệt tháng 4 năm 2019, tr30-38. * Tác giả chịu trách nhiệm chính 2. Vu Thi Thu Trang, Phan Thu Phuong, Nguyen Tuan Tung, Vu Van Truong, Nguyen Huy Binh, Pham Cam Phuong, Nguyen Thanh Thuy, Dao Ngoc Phu, Dang Thanh Do, Nguyen Duc Nghia, Vu Van Giap, Ngo Quy Chau (2020).
“Clinical effects of autologous bone marrow derived stem cell therapy for patients with chronic obstructive pulmonary disease at Bach Mai hospital”. Journal Of Medical Research 136 (12) – 2020: p99-109.“Quality and safety of autologous bone marrow derived stem cell separation procedure in chronic obstructive pulmonary disease patients”. Journal of functional ventilation and pulmonology, Issue 36 Volume 12, 4/2021, p1-6. * Correspondent author 1 INTRODUCTION Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide.
Although the disease progresses slowly, is chronic in nature and does not cause death at an early stage, the consequences caused by the disease to the patients, families and society are very severe. In the advanced stages of the disease, the patient becomes disabled, severely impaired in health and quality of life, even with treatment. Today, the drugs to treat the disease are increasingly optimized, but they do not work to prevent the pathogenesis of COPD. The disease continues to progress to severe stages, eventually to death.
Stem cells with characteristics such as high differentiation ability, immunoregulatory ability, tissue regeneration. are expected to bring benefits to patients and improve quality of life. In Vietnam as well as in the world, the number of studies applying stem cells therapy in general and bone marrow (BM) stem cells in particular in the treatment of COPD is still small and the follow-up time is limited. In addition, autologous BM stem cell sources have been studied in normal people and in the treatment of some diseases, but there have been no studies evaluating the characteristics of bone marrow stem cells in patients with COPD.
Therefore, we conducted a study on the topic "Application of autologous bone marrow stem cells in chronic obstructive pulmonary disease management" with two objectives: 1. Characterization of bone marrow fluid and autologous bone marrow stem cell grafts of patients with COPD. Outcomes of application of autologous BM stem cells therapy in COPD management. Necessity of the thesis: The prevalence of moderate and severe COPD in Vietnam ranks highest in the Asia Pacific region, accounting for 6.7% of the population.
In the near future, the burden of COPD will still tend to increase, due to continued exposure to risk factors and an aging population. Current measures to treat COPD include: stopping exposure to risk factors, using drugs (bronchodilators, corticosteroids, phosphodiesterase 4 inhibitors.), pulmonary rehabilitation, oxygen support, mechanical ventilation. However, despite comprehensive and optimized treatment, the disease continues to progress over time. Therefore, an urgent need today is to find new treatments with the ambition of stopping or even reversing the course of the disease.
In recent years 2 in the world, there have been many studies on the use of stem cells in the treatment of various diseases including respiratory diseases such as pulmonary fibrosis, COPD. However, the number of studies and follow-up time of clinical trials on stem cells therapy are still limited, there are many questions about the safety and mechanism of action of exogenous cells after being introduced into chronic damaged lungs still needs to be answered. New contribution of the thesis: This is the first study to apply autologous BM stem cell therapy in the treatment of COPD, conducted in Vietnam. The study results provide indicators on the characteristics of bone marrow fluid, nucleated and mononuclear cell composition in the bone marrow fluid of patients with COPD as well as characteristics of autologous bone marrow stem cell graft of patients with COPD.
The study demonstrates the safety of autologous stem cell therapy from bone marrow for COPD treatment, as well as the initial results of the therapy when treating COPD patients. The thesis also provides scientific data as a basis for further studies. Thesis outline: The thesis consists of 119 pages, covering: introduction (2 pages), overview (39 pages), object and method of research (21 pages), results (27 pages), discussion (28 pages), conclusion (2 pages). It has 48 tables, 7 figures, 2 charts.
154 References, including English and Vietnamese versions CHAPTER 1: OVERVIEW 1. Overview of COPD COPD definition According to the definition of the Global Initiative on COPD (GOLD), COPD is a common preventable and treatable disease, characterized by chronic airflow obstruction, often progressive with a progressive response. Excessive chronic inflammatory response in the respiratory tract and lung parenchyma to noxious particles or gases. COPD pathogenesis The pathogenesis of COPD is very complex, in which inflammatory factors play a central role.
The hallmark of COPD is frequent, excessive inflammation of the entire airways and lung parenchyma. This inflammatory reaction is much more amplified than the usual inflammatory responses of the airways. Cells involved in the 3 inflammatory response release a variety of inflammatory mediators that chemotaxis other inflammatory cells and proinflammatory mediators that amplify inflammation and promote tissue remodeling, change the normal structure and function of the lung. Imbalance of Proteinase - Proteinase inhibitors is the most important pathogenesis of the development of pulmonary emphysema and loss of lung elasticity.
In COPD the balance is tilted towards increased proteolysis or increased proteinase. Oxidative activation not only damages lung tissue but also participates in the imbalance of protease - anti-protease. Antioxidants also support inflammation by promoting the activity of genes that produce inflammatory chemical mediators such as IL-8, TNF-. COPD diagnosis Thoroughly explore the history of exposure to risk factors for the disease, perform a clinical examination to find diagnostic-oriented signs such as a history of exposure to risk factors (smoking, dust smoke), history of cough.
, chronic sputum production or persistent dyspnea, increasing with exertion. Spirometry is the gold standard for diagnosing and assessing the degree of airway obstruction in patients with COPD. Diagnosis is confirmed when the obstructive disorder does not completely recover after the bronchodilator test: the FEV1/FVC index < 70% after the test. Stem cells and sources of stem cells Definition Stem cells are unspecialized cells that can self-renewal and can also differentiate into more mature cells with specialized functions.
In humans, stem cells have been found in early embryos; in some fetal tissues, umbilical cord and placenta; and in some mature organs. Sources of stem cells: embryonic stem cells, fetal stem cells, adult stem cells. Bone marrow stem cells Bone marrow is the home of hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), endothelial stem/progenitor cells (EPCs), and a few other rare types of stem cells. In which, HSC and MSC have been studied and applied widely.
4 Bone marrow MSCs Definition of MSC embryo, which originates mainly in the mesoderm and makes up the majority of connective tissue cells in the adult body. Mesenchymal Stem Cells (MSCs) are multipotent stromal cells that can differentiate into many different cell types of connective tissue including osteoblasts, chondrocytes, muscle cells, and stromal cells. fat cells, etc. Criterias of MSC The International Society for Cell Therapeutics (ISCT) Committee on Tissue and MSCs has proposed a set of standards for this cell type, including: MSC must be plastic-adherent when maintained in standard culture conditions.
MSC must express CD105, CD73 and CD90, and lack expression of CD45, -DR surface molecules. MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. BM MSCs characteristics Human MSCs are usually isolated from the mononuclear cell layer of the bone marrow. Besides regenerative potential, MSCs have been shown to have anti- inflammatory, immunomodulatory properties.
The anti-inflammatory activity of MSCs can be attributed to the reduction of lymphocyte proliferation, natural killer and dendritic cells, and related chemical mediators: TGF- IL-10 and NO. MSCs have immunosuppressive ability, modulating the function of T cells and B cells. MSC also has the ability to modulate immunity through the effect of reducing the maturation and function of dendritic cells, inhibiting dendritic cells. proliferation, differentiation and chemotaxis of B cells in vitro.
5 Producing BM stem cells graft protocol Collection of BM stem cells BM stem cells extraction: manually or automatically. Stem cells preservation Fresh stem cell grafts After collection, stem cells are stored at 4°C for a maximum of 72 hours and then infuse to the patient. This method is usually applied to facilities that do not have sufficient conditions to be able to store stem cells for a long time. Cryopreserved stem cell grafts After being collected, if the storage period is longer than 3 days, it is frozenized and stored at -80oC or lower.
The stem cells grafts were stored for a long time at sub- zero temperatures (-196oC), in liquid nitrogen. Thawing and infusion of stem cells to the patient Evaluation and quality control of stem cell grafts Nucleated cells count Count the percentage of viable cells by Trypan Blue staining method Cluster culture Identification of live CD34+ and MSC cells by flow cytometry Determine the state of infection 1. Application of autologous BM stem cells in COPD management 1. Pre-clinical trials In general, the studies showing the effectiveness of the treatment of COPD in experimental animals are mainly attributed to the chemical mediators secreted by MSCs.
These substances reduce the inflammatory response, modulate the immune response, improve epithelial and endothelial cell permeability, and promote tissue damage repair. In addition, some pneumocytes are regenerated, which can also contribute to amelioration of the disease. These preclinical studies demonstrate the therapeutic potential of MSCs with COPD in humans. Clinical trials applying BM stem cells in COPD Figure 0.
Clinical trials applying BM stem cells in COPD Trial Phase Stem cells Number Results Weiss và cs 2 Allogeneic BM 62 COPD No toxicity or serious MSC vs placebo patients, events or deaths. 6 Trial Phase Stem cells Number Results 1x108cells/1 moderate There was no infusion and severe difference in lung Once a month in 4 function or quality of months life compared with the control group Decrease in CRP 1 month after infusion. Ribeiro-Paes 1 Autologous BM 4 severe No side effects và cs MSC 1x108 COPD Little improvement in cells/kg, single patients respiratory function, infusion little improvement in health status and quality of life Stolk và cs 1 Autologous BM 7 COPD No side effects MSC 1- patients, Alveolar membrane 2x106cells/kg severe and increases CD31 cell Twice, 1 week much expression apart severe 1. Clinical trials applying stem cells in COPD in Vietnam In 2015, Le Thi Bich Phuong et al conducted a pilot study, without a control group at Van Hanh Hospital (Ho Chi Minh City), Military Hospital 103, National Lung Hospital, initially evaluate the role of mesenchymal stem cells from allogeneic umbilical cord in the treatment of COPD in 20 patients.
Umbilical cord-derived mesenchymal stem cells (UC-MSCs) were collected from umbilical cord samples from donors at birth.