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Hanna M, Elnassag SS, Mohamed DH, Elbaset MA, Shaker O, Khowailed EA, Gouda SAA. Melatonin and mesenchymal stem cells co-administration alleviates chronic obstructive pulmonary disease via modulation of angiogenesis at the vascular-alveolar unit. Pflugers Arch 2024; 476:1155-1168. [PMID: 38740599 PMCID: PMC11166745 DOI: 10.1007/s00424-024-02968-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/31/2024] [Accepted: 04/25/2024] [Indexed: 05/16/2024]
Abstract
Chronic obstructive pulmonary disease (COPD) is considered a severe disease mitigating lung physiological functions with high mortality outcomes, insufficient therapy, and pathophysiology pathways which is still not fully understood. Mesenchymal stem cells (MSCs) derived from bone marrow play an important role in improving the function of organs suffering inflammation, oxidative stress, and immune reaction. It might also play a role in regenerative medicine, but that is still questionable. Additionally, Melatonin with its known antioxidative and anti-inflammatory impact is attracting attention nowadays as a useful treatment. We hypothesized that Melatonin may augment the effect of MSCs at the level of angiogenesis in COPD. In our study, the COPD model was established using cigarette smoking and lipopolysaccharide. The COPD rats were divided into four groups: COPD group, Melatonin-treated group, MSC-treated group, and combined treated group (Melatonin-MSCs). We found that COPD was accompanied by deterioration of pulmonary function tests in response to expiratory parameter affection more than inspiratory ones. This was associated with increased Hypoxia inducible factor-1α expression and vascular endothelial growth factor level. Consequently, there was increased CD31 expression indicating increased angiogenesis with massive enlargement of airspaces and thinning of alveolar septa with decreased mean radial alveolar count, in addition to, inflammatory cell infiltration and disruption of the bronchiolar epithelial wall with loss of cilia and blood vessel wall thickening. These findings were improved significantly when Melatonin and bone marrow-derived MSCs were used as a combined treatment proving the hypothesized target that Melatonin might augment MSCs aiming at vascular changes.
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Affiliation(s)
- Mira Hanna
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt.
| | - Sabreen Sayed Elnassag
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Dina Hisham Mohamed
- Department of Histology, Faculty of Medicine, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Marawan Abd Elbaset
- Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Olfat Shaker
- Department of Biochemistry, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Effat A Khowailed
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
| | - Sarah Ali Abdelhameed Gouda
- Department of Medical Physiology, Faculty of Medicine, Kasr Al-Ainy, Cairo University, El-Maniel 11451, Cairo, Egypt
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Iwatake M, Nagamura-Inoue T, Doi R, Tanoue Y, Ishii M, Yukawa H, Matsumoto K, Tomoshige K, Nagayasu T, Tsuchiya T. Designer umbilical cord-stem cells induce alveolar wall regeneration in pulmonary disease models. Front Immunol 2024; 15:1384718. [PMID: 38745668 PMCID: PMC11091323 DOI: 10.3389/fimmu.2024.1384718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/02/2024] [Indexed: 05/16/2024] Open
Abstract
Background Researchers are focusing on cellular therapy for chronic obstructive pulmonary disease (COPD) using mesenchymal stem cells (MSCs), with human bone marrow-derived MSCs (hBM-MSCs) leading the way. However, BM-MSCs may not be as optimal as therapeutic cells owing to their low growth potential, invasive harvesting, and high expression of aging-related genes with poor differentiation potential. Consequently, umbilical cord-derived MSCs (hUC-MSCs), which have many excellent features as allogeneic heterologous stem cells, have received considerable attention. Allogeneic and heterologous hUC-MSCs appear to be promising owing to their excellent therapeutic properties. However, MSCs cannot remain in the lungs for long periods after intravenous infusion. Objective To develop designer hUC-MSCs (dUC-MSCs), which are novel therapeutic cells with modified cell-adhesion properties, to aid COPD treatment. Methods dUC-MSCs were cultured on type-I collagen gels and laminin 411, which are extracellular matrices. Mouse models of elastase-induced COPD were treated with hUC-MSCs. Biochemical analysis of the lungs of treated and control animals was performed. Results Increased efficiency of vascular induction was found with dUC-MSCs transplanted into COPD mouse models compared with that observed with transplanted hUC-MSCs cultured on plates. The transplanted dUC-MSCs inhibited apoptosis by downregulating pro-inflammatory cytokine production, enhancing adhesion of the extracellular matrix to alveolar tissue via integrin β1, promoting the polarity of M2 macrophages, and contributing to the repair of collapsed alveolar walls by forming smooth muscle fibers. dUC-MSCs inhibited osteoclastogenesis in COPD-induced osteoporosis. hUC-MSCs are a promising cell source and have many advantages over BM-MSCs and adipose tissue-derived MSCs. Conclusion We developed novel designer cells that may be involved in anti-inflammatory, homeostatic, injury repair, and disease resistance processes. dUC-MSCs repair and regenerate the alveolar wall by enhancing adhesion to the damaged site. Therefore, they can contribute to the treatment of COPD and systemic diseases such as osteoporosis.
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Affiliation(s)
- Mayumi Iwatake
- Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya, Japan
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tokiko Nagamura-Inoue
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Ryoichiro Doi
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yukinori Tanoue
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsutoshi Ishii
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroshi Yukawa
- Institute of Nano-Life-Systems, Institutes of Innovation for Future Society, Nagoya University, Nagoya, Japan
| | - Keitaro Matsumoto
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Koichi Tomoshige
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takeshi Nagayasu
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoshi Tsuchiya
- Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Thoracic Surgery, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan
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Wang X, Tian H, Yang X, Zhao H, Liang X, Li Y. Mesenchymal Stem Cells‐Derived Extracellular Vesicles in Orthopedic Diseases: Recent Advances and Therapeutic Potential. ADVANCED THERAPEUTICS 2023; 6. [DOI: 10.1002/adtp.202300193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Indexed: 01/06/2025]
Abstract
AbstractEver since the first application of mesenchymal stem cell (MSC) transplantation treating human hematologic malignancies in 1995, MSC‐based treatments have demonstrated great therapeutic potential in clinical settings. However, only a few MSC‐based cell therapy products have been clinically approved. Accumulating evidence suggests that the beneficial effects of MSCs are mainly attributed to the release of paracrine factors or extracellular vesicles (EVs) rather than their mesodermal differentiation potential. Therefore, MSC‐derived EVs (MSC‐EVs), such as exosomes and microvesicles, have merged as promising alternatives to traditional cell‐based therapeutics in clinical practice. They offer several advantages such as better safety, lower immunogenicity, protection of cargoes from degradation, and the ability to overcome biological barriers. Moreover, there have been multiple clinical studies exploring the potential of MSC‐EVs for treating various diseases, including orthopedic disorders. However, there is no definitive “cure” for conditions such as osteoporosis and other bone disorders, but MSC‐EVs have displayed significant therapeutic potential for these orthopedic ailments. Therefore, the objective of this study is to conduct a systematic review of current knowledge related to MSC‐EVs and emphasize their potential application in treating orthopedic diseases, such as bone defects, osteoarthritis, osteoporosis, intervertebral disc degeneration, osteosarcoma, and osteoradionecrosis.
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Affiliation(s)
- Xinwen Wang
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Haodong Tian
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Xinquan Yang
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Hongmou Zhao
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Xiaojun Liang
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
| | - Yi Li
- Department of Foot and Ankle Surgery, Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi Province 710054 P. R. China
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Guarnier LP, Moro LG, Lívero FADR, de Faria CA, Azevedo MF, Roma BP, Albuquerque ER, Malagutti-Ferreira MJ, Rodrigues AGD, da Silva AA, Sekiya EJ, Ribeiro-Paes JT. Regenerative and translational medicine in COPD: hype and hope. Eur Respir Rev 2023; 32:220223. [PMID: 37495247 PMCID: PMC10369169 DOI: 10.1183/16000617.0223-2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 05/23/2023] [Indexed: 07/28/2023] Open
Abstract
COPD is a common, preventable and usually progressive disease associated with an enhanced chronic inflammatory response in the airways and lung, generally caused by exposure to noxious particles and gases. It is a treatable disease characterised by persistent respiratory symptoms and airflow limitation due to abnormalities in the airways and/or alveoli. COPD is currently the third leading cause of death worldwide, representing a serious public health problem and a high social and economic burden. Despite significant advances, effective clinical treatments have not yet been achieved. In this scenario, cell-based therapies have emerged as potentially promising therapeutic approaches. However, there are only a few published studies of cell-based therapies in human patients with COPD and a small number of ongoing clinical trials registered on clinicaltrials.gov Despite the advances and interesting results, numerous doubts and questions remain about efficacy, mechanisms of action, culture conditions, doses, timing, route of administration and conditions related to homing and engraftment of the infused cells. This article presents the state of the art of cell-based therapy in COPD. Clinical trials that have already been completed and with published results are discussed in detail. We also discuss the questions that remain unanswered about cell-based regenerative and translational medicine for COPD.
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Affiliation(s)
- Lucas Pires Guarnier
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | - Lincoln Gozzi Moro
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
- Biomedical Sciences Institute, Butantan Institute, Technological Research Institute, University of São Paulo (USP), São Paulo, Brazil
| | | | | | - Mauricio Fogaça Azevedo
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | - Beatriz Pizoni Roma
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | | | - Maria José Malagutti-Ferreira
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
| | | | - Adelson Alves da Silva
- São Lucas Research and Education Institute (IEP - São Lucas), TechLife, São Paulo, Brazil
| | - Eliseo Joji Sekiya
- São Lucas Research and Education Institute (IEP - São Lucas), TechLife, São Paulo, Brazil
| | - João Tadeu Ribeiro-Paes
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, Brazil
- Laboratory of Genetics and Cell Therapy - GenTe Cel, Department of Biotechnology, São Paulo State University (UNESP), Assis, Brazil
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Wang Y, Gao T, Wang B. Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Res Ther 2023; 14:260. [PMID: 37726805 PMCID: PMC10510299 DOI: 10.1186/s13287-023-03497-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
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Affiliation(s)
- Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Tianyun Gao
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China.
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Gong Z, Li Q, Shi J, Li P, Hua L, Shultz LD, Ren G. Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis. Sci Immunol 2023; 8:eadd5204. [PMID: 36800412 PMCID: PMC10067025 DOI: 10.1126/sciimmunol.add5204] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 01/25/2023] [Indexed: 02/19/2023]
Abstract
Neutrophils, the most abundant innate immune cells, function as crucial regulators of the adaptive immune system in diverse pathological conditions, including metastatic cancer. However, it remains largely unknown whether their immunomodulatory functions are intrinsic or acquired within the pathological tissue environment. Here, using mouse models of metastatic breast cancer in the lungs, we show that, although neutrophils isolated from bone marrow (BM) or blood are minimally immunosuppressive, lung-infiltrating neutrophils are robustly suppressive of both T cells and natural killer (NK) cells. We found that this tissue-specific immunosuppressive capacity of neutrophils exists in the steady state and is reinforced by tumor-associated inflammation. Acquisition of potent immunosuppression activity by lung-infiltrating neutrophils was endowed by the lung-resident stroma, specifically CD140a+ mesenchymal cells (MCs) and largely via prostaglandin-endoperoxide synthase 2 (PTGS2), the rate-limiting enzyme for prostaglandin E2 (PGE2) biosynthesis. MC-specific deletion of Ptgs2 or pharmacological inhibition of PGE2 receptors reversed lung neutrophil-mediated immunosuppression and mitigated lung metastasis of breast cancer in vivo. These lung stroma-targeting strategies substantially improved the therapeutic efficacy of adoptive T cell-based immunotherapy in treating metastatic disease in mice. Collectively, our results reveal that the immunoregulatory effects of neutrophils are induced by tissue-resident stroma and that targeting tissue-specific stromal factors represents an effective approach to boost tissue-resident immunity against metastatic disease.
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Affiliation(s)
- Zheng Gong
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | - Qing Li
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | - Jiayuan Shi
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | - Peishan Li
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | - Li Hua
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
| | | | - Guangwen Ren
- The Jackson Laboratory, Bar Harbor, ME 04609, USA
- Tufts University School of Medicine, Boston, MA 02111, USA
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA
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Hsu CN, Lin YT, Chen YH, Tseng TY, Tsai HF, Hong SG, Yao CL. An Aligned Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Scaffold Fixed with Fibronectin to Enhance the Attachment and Growth of Human Endothelial Progenitor Cells. BIOTECHNOL BIOPROC E 2023. [DOI: 10.1007/s12257-022-0255-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Robinson AM, Stavely R, Miller S, Eri R, Nurgali K. Mesenchymal stem cell treatment for enteric neuropathy in the Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res 2022; 389:41-70. [PMID: 35536444 DOI: 10.1007/s00441-022-03633-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 04/26/2022] [Indexed: 11/30/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic gut inflammation with periods of acute flares and remission. Beneficial effects of a single dose of mesenchymal stem cell (MSC)-based treatment have been demonstrated in acute models of colitis. No studies investigated therapeutic effects of MSCs for the attenuation of enteric neuropathy in a chronic model of colitis. The short and long-term effects of MSC treatment in modulating inflammation and damage to the enteric nervous system (ENS) were studied in the Winnie mouse model of spontaneous chronic colitis highly representative of human IBD. Winnie mice received a single dose of either 1 × 106 human bone marrow-derived MSCs or 100µL PBS by intracolonic enema. C57BL/6 mice received 100µL PBS. Colon tissues were collected at 3 and 60 days post MSC administration to evaluate the short-term and long-term effects of MSCs on inflammation and enteric neuropathy by histological and immunohistochemical analyses. In a separate set of experiments, multiple treatments with 4 × 106 and 2 × 106 MSCs were performed and tissue collected at 3 days post treatment. Chronic intestinal inflammation in Winnie mice was associated with persistent diarrhea, perianal bleeding, morphological changes, and immune cell infiltration in the colon. Significant changes to the ENS, including impairment of cholinergic, noradrenergic and sensory innervation, and myenteric neuronal loss were prominent in Winnie mice. Treatment with a single dose of bone marrow-derived MSCs was ineffective in attenuating chronic inflammation and enteric neuropathy in Winnie.
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Affiliation(s)
- Ainsley M Robinson
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rhian Stavely
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia.,Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Sarah Miller
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia
| | - Rajaraman Eri
- University of Tasmania, School of Health Sciences, Launceston, TAS, Australia
| | - Kulmira Nurgali
- Institute for Health and Sport, Victoria University; Western Centre for Health, Research and Education, Sunshine Hospital, Melbourne, VIC, Australia. .,Department of Medicine Western Health, The University of Melbourne, Melbourne, VIC, Australia. .,Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia.
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9
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Identification and functional characterization of CD133+GFAP+CD117+Sca1+ neural stem cells. Mol Cell Biochem 2022; 477:897-914. [DOI: 10.1007/s11010-021-04339-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 12/15/2021] [Indexed: 02/03/2023]
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Squassoni SD, Sekiya EJ, Fiss E, Lapa MS, Cayetano DDS, Nascimento F, Alves A, Machado NC, Escaramboni B, Lívero FADR, Malagutti-Ferreira MJ, Soares MR, Dos Santos Figueiredo FW, Kramer BKN, Zago PMJJ, Ribeiro-Paes JT. Autologous Infusion of Bone Marrow and Mesenchymal Stromal Cells in Patients with Chronic Obstructive Pulmonary Disease: Phase I Randomized Clinical Trial. Int J Chron Obstruct Pulmon Dis 2022; 16:3561-3574. [PMID: 35002228 PMCID: PMC8733220 DOI: 10.2147/copd.s332613] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 12/06/2021] [Indexed: 12/23/2022] Open
Abstract
Background and Objectives Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar walls, chronic inflammation and persistent respiratory symptoms. There is no curative clinical treatment for COPD. In this context, cell-based therapy is a promising therapeutic alternative for COPD. Thus, in this open, controlled and randomized Phase I Clinical Trial, we aimed to assess the safety of the infusion of autologous bone marrow mononuclear cells (BMMC), adipose-derived mesenchymal stromal cells (ADSC) and, especially, the safety of concomitant infusion (co-infusion) of BMMC and ADSC as a new therapeutic alternative for COPD. The rationale for co-infusion of BMMC and ADSC is based on the hypothesis of an additive or synergistic therapeutic effect resulting from this association. Methods To achieve the proposed objectives, twenty patients with moderate-to-severe COPD were randomly divided into four groups: control group - patients receiving conventional treatment; BMMC group - patients receiving only BMMC; ADSC group - patients receiving only ADSC, and co-infusion group - patients receiving the concomitant infusion of BMMC and ADSC. Patients were assessed for pulmonary function, biochemical profile, and quality of life over a 12 months follow-up. Results No adverse events were detected immediately after the infusion of BMMC, ADSC or co-infusion. In the 12-month follow-up, no causal relationship was established between adverse events and cell therapy procedures. Regarding the efficacy, the BMMC group showed an increase in forced expiratory volume (FEV1) and diffusing capacity for carbon monoxide (DLCO). Co-infusion group showed a DLCO, and gas exchange improvement and a better quality of life. Conclusion The results obtained allow us to conclude that cell-based therapy with co-infusion of BMMC and ADSC is a safe procedure and a promising therapeutic for COPD. However, additional studies with a greater number of patients are needed before randomized and controlled Phase III clinical trials can be implemented.
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Affiliation(s)
| | - Eliseo Joji Sekiya
- São Lucas Research and Education Institute (IEP-Sao Lucas), TechLife, São Paulo, SP, Brazil
| | - Elie Fiss
- ABC Medical School, São Paulo, SP, Brazil.,Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brazil
| | | | | | - Flávia Nascimento
- São Lucas Research and Education Institute (IEP-Sao Lucas), TechLife, São Paulo, SP, Brazil
| | - Adelson Alves
- São Lucas Research and Education Institute (IEP-Sao Lucas), TechLife, São Paulo, SP, Brazil
| | | | | | | | | | - Murilo Racy Soares
- Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil
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11
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Arruda de Faria C, Silva Júnior WA, Caetano Andrade Coelho KB, Bassi M, Colombari E, Zanette DL, Ribeiro-Paes JT. Mesenchymal stromal cells-based therapy in a murine model of elastase-induced emphysema: Simvastatin as a potential adjuvant in cellular homing. Pulm Pharmacol Ther 2021; 70:102075. [PMID: 34428598 DOI: 10.1016/j.pupt.2021.102075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/31/2021] [Accepted: 08/18/2021] [Indexed: 12/01/2022]
Abstract
Chronic Obstructive Pulmonary Disease - COPD is characterized by the destruction of alveolar walls associated to a chronic inflammatory response of the airways. There is no clinical therapy for COPD. In this context, cell-based therapies represent a promising therapeutic approach for chronic lung disease. The goal of this work was to evaluate the effect of simvastatin on cell-based therapy in a mice emphysema model. Female FVB mice received intranasal instillation of elastase (three consecutive doses of 50 μL) in order to promote pulmonary emphysema. After 21 days of the first instillation, the animals were treated with Adipose-Derived Mesenchymal Stromal Cells (AD-MSC, 2.6 × 106) via retro-orbital infusion associated or not with simvastatin administrated daily via oral gavage (15 mg/kg/15d). Before and after these treatments, the histological and morphometrical analyses of the lung tissue, as so as lung function (whole body plethysmography) were evaluated. PAI-1 gene expression, an upregulated factor by ischemia that indicate a low survival of transplanted MSC, was also evaluated. The result regarding morphological and functional aspects of both lungs, presented no significant difference among the groups (AD-MSC or AD-MSC + Simvastatin). However, significant anatomical difference was observed in the right lung of the both groups of mice. The results shown a higher deposition of cells in the right lung, with might to be explained by anatomical differences (slightly higher right bronchi). Decreased levels of PAI-1 were observed in the simvastatin treated groups. The pulmonary ventilation was similar between the groups with only a tendency to a lower in the elastase treated animals due to a low respiratory frequency. In conclusion, the results suggest that both AD-MSC and simvastatin treatments could promote an improvement of morphological recovery of pulmonary emphysema, that it was more pronounced in the right lung.
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Affiliation(s)
- Carolina Arruda de Faria
- Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo - USP, Ribeirão Preto, São Paulo, Brazil
| | - Wilson Araújo Silva Júnior
- Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo - USP, Ribeirão Preto, São Paulo, Brazil
| | | | - Mirian Bassi
- Departamento de Fisiologia e Patologia, Faculdade de Odontologia, Universidade Estadual Paulista - Unesp, Araraquara, São Paulo, Brazil
| | - Eduardo Colombari
- Departamento de Fisiologia e Patologia, Faculdade de Odontologia, Universidade Estadual Paulista - Unesp, Araraquara, São Paulo, Brazil
| | - Dalila Lucíola Zanette
- Laboratório de Ciências e Tecnologias Aplicadas em Saúde, Instituto Carlos Chagas, Fiocruz Paraná, Curitiba, Paraná, Brazil
| | - João Tadeu Ribeiro-Paes
- Departamento de Biotecnologia, Universidade Estadual Paulista - Unesp, Assis, São Paulo, Brazil.
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Abdul Halim NSS, Yahaya BH, Lian J. Therapeutic Potential of Adipose-Derived Stem Cells in the Treatment of Pulmonary Diseases. Curr Stem Cell Res Ther 2021; 17:103-112. [PMID: 34387168 DOI: 10.2174/1574888x16666210812145202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 05/07/2021] [Accepted: 05/25/2021] [Indexed: 11/22/2022]
Abstract
Stem cells derived from adipose tissues (ADSCs) have emerged as an ideal candidate for various models of respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome. ADSCs have qualities that may make them better suited for treating inflammatory lung diseases than other MSCs. ADSCs show a lower senescence ratio, higher proliferative capacity and stability in terms of their genetic and morphology during long-term culture over bone marrow-derived mesenchymal stem cells (BMMSCs). With advanced research techniques, the advantageous effects of ADSCs seem limited to their ability to engraft, differentiate, and be related to their secretion of trophic factors. These trophic factors regulate the therapeutic and regenerative outcomes in various lung inflammatory diseases. Taken together, these particular qualities of ADSCs make them significantly relevant for clinical applications. This article discusses a recent advance of ADSCs biology and their translational application emphasizing their anti-inflammatory, immunomodulatory and regenerative properties particularly on lung inflammatory diseases. Besides, the relevant advancements made in the field, the regulatory aspects, and other challenges and obstacles will be highlighted.
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Affiliation(s)
- Nur Shuhaidatul Sarmiza Abdul Halim
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Penang . Malaysia
| | - Badrul Hisham Yahaya
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Penang . Malaysia
| | - Jie Lian
- Lung Stem Cell and Gene Therapy Group, Regenerative Medicine Cluster, Advanced Medical and Dental Institute (IPPT), SAINS@BERTAM, Universiti Sains Malaysia, 13200 Kepala Batas, Penang . Malaysia
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13
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Glassberg MK, Csete I, Simonet E, Elliot SJ. Stem Cell Therapy for COPD: Hope and Exploitation. Chest 2021; 160:1271-1281. [PMID: 33894254 DOI: 10.1016/j.chest.2021.04.020] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 04/05/2021] [Accepted: 04/11/2021] [Indexed: 12/21/2022] Open
Abstract
COPD is a chronic inflammatory and destructive disease characterized by progressive decline in lung function that can accelerate with aging. Preclinical studies suggest that mesenchymal stem cells (MSCs) may provide a therapeutic option for this incurable disease because of their antiinflammatory, reparative, and immunomodulatory properties. To date, clinical trials using MSCs demonstrate safety in patients with COPD. However, because of the notable absence of large, multicenter randomized trials, no efficacy or evidence exists to support the possibility that MSCs can restore lung function in patients with COPD. Unfortunately, the investigational status of cell-based interventions for lung diseases has not hindered the propagation of commercial businesses, exploitation of the public, and explosion of medical tourism to promote unproven and potentially harmful cell-based interventions for COPD in the United States and worldwide. Patients with COPD constitute the largest group of patients with lung disease flocking to these unregulated clinics. This review highlights the numerous questions and concerns that remain before the establishment of cell-based interventions as safe and efficacious treatments for patients with COPD.
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Affiliation(s)
- Marilyn K Glassberg
- Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ.
| | | | | | - Sharon J Elliot
- Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ; University of Miami Miller School of Medicine, Miami, FL
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14
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Lin F, Ichim TE, Pingle S, Jones LD, Kesari S, Ashili S. Mesenchymal stem cells as living anti-inflammatory therapy for COVID-19 related acute respiratory distress syndrome. World J Stem Cells 2020; 12:1067-1079. [PMID: 33178392 PMCID: PMC7596438 DOI: 10.4252/wjsc.v12.i10.1067] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/13/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), is growing at an exponential rate worldwide. Manifestations of this disease are heterogeneous; however, advanced cases often exhibit various acute respiratory distress syndrome-like symptoms, systemic inflammatory reactions, coagulopathy, and organ involvements. A common theme in advanced COVID-19 is unrestrained immune activation, classically referred to as a “cytokine storm”, as well as deficiencies in immune regulatory mechanisms such as T regulatory cells. While mesenchymal stem cells (MSCs) themselves are objects of cytokine regulation, they can secrete cytokines to modulate immune cells by inducing anti-inflammatory regulatory Treg cells, macrophages and neutrophils; and by reducing the activation of T and B cells, dendritic and nature killer cells. Consequently, they have therapeutic potential for treating severe cases of COVID-19. Here we discuss the unique ability of MSCs, to act as a “living anti-inflammatory”, which can “rebalance” the cytokine/immune responses to restore equilibrium. We also discuss current MSC trials and present different concepts for optimization of MSC therapy in patients with COVID-19 acute respiratory distress syndrome.
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Affiliation(s)
- Feng Lin
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Thomas E Ichim
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Sandeep Pingle
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Lawrence D Jones
- Research and Development, CureScience, San Diego, CA 92121, United States
| | - Santosh Kesari
- Cancer Center, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, United States
| | - Shashaanka Ashili
- Research and Development, CureScience, San Diego, CA 92121, United States
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15
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Lanzoni G, Linetsky E, Correa D, Alvarez RA, Marttos A, Hirani K, Cayetano SM, Castro JG, Paidas MJ, Efantis Potter J, Xu X, Glassberg M, Tan J, Patel AN, Goldstein B, Kenyon NS, Baidal D, Alejandro R, Vianna R, Ruiz P, Caplan AI, Ricordi C. Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS). CELLR4-- REPAIR, REPLACEMENT, REGENERATION, & REPROGRAMMING 2020; 8. [PMID: 34164564 DOI: 10.32113/cellr4_20204_2839] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer's Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (l00 × 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).
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Affiliation(s)
- G Lanzoni
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - E Linetsky
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Correa
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - R A Alvarez
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - A Marttos
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA
| | - K Hirani
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - S Messinger Cayetano
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - J G Castro
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - M J Paidas
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - J Efantis Potter
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - X Xu
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - M Glassberg
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - J Tan
- Organ Transplant Institute, Fuzhou General Hospital, Xiamen University, Fuzhou, China
| | - A N Patel
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.,HCA Research Institute, Nashville, TN, USA
| | - B Goldstein
- Department of Head and Neck Surgery and Communication Sciences, Duke University, Durham, NC, USA
| | - N S Kenyon
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Baidal
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - R Alejandro
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - R Vianna
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA.,Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - P Ruiz
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA.,Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - A I Caplan
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - C Ricordi
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA
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16
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Gülhan PY, Ekici MS, Niyaz M, Gülhan M, Erçin ME, Ekici A, Aksoy N. Therapeutic Treatment with Abdominal Adipose Mesenchymal Cells Does Not Prevent Elastase-Induced Emphysema in Rats. Turk Thorac J 2020; 21:14-20. [PMID: 32163359 PMCID: PMC7020897 DOI: 10.5152/turkthoracj.2019.180136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 02/06/2019] [Indexed: 11/22/2022]
Abstract
OBJECTIVES Emphysema and chronic bronchitis have different pathophysiologies but both are significant components of chronic obstructive lung disease (COPD). The levels of Matrix metalloproteinase (MMP)-9 in the bronchoalveloar lavage fluid (BALF) and in serum indicate the presence of emphysema. Intratracheal administration of elastase has been used to create a rat model of emphysema. Adipose tissue-derived mesenchymal stem cells (MSC) have been postulated to prevent or reverse emphysema, however, this has not been examined in the rat model of elastase-induced emphysema. MATERIALS AND METHODS In this study, 31 Wistar albino rats aged 6-8 weeks and weighing 250-300 g were assessed. On day 1, the animals were treated intratracheally with 0.5 mL saline (control group, n=10), i.e., 0.5 mL saline solution containing 0.1 IU porcine pancreatic elastase (PPE) (Elastase group, n=12) or PPE plus MSC (Elastase-MSC group, n=9) was adminstered per animal. MSCs suspended in serum were injected via the caudal vein on day 21. At least 106 cells were injected. All animals were sacrificed on day 42 and the emphysema index (EI) was calculated, along with measuring the BALF and serum MMP-9 concentrations. RESULTS Porcine pancreatic elastase induced a significant degree of emphysema in the PPE groups as compared to the control group, which was determined by the EI index (p=0.008). This was not reversed by MSC treatment. The EI remained significantly low in comprison with the controls (p=0.001) and measured no different from the Elastase-treated animals. There was no statistically significant difference between the BALF and serum MMP-9 levels between the control and treatment groups. CONCLUSION Our findings suggest that therapeutic treatment with adipose tissue-derived MSC in rats has no effect on emphysema or on MMP9 expression, which is a known marker of emphysema.
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Affiliation(s)
- Pınar Yıldız Gülhan
- Department of Chest Diseases, Düzce University School of Medicine, Düzce, Turkey
| | - Mehmet Savaş Ekici
- Department of Chest Diseases, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - Mehmet Niyaz
- Clinic of Cardiovascular Surgery, Bartın State Hospital, Bartın, Turkey
| | - Muhammet Gülhan
- Clinic of Infectious Diseases and Clinical Microbiology, Tosya State Hospital, Kastamonu, Turkey
| | - Mustafa Emre Erçin
- Department of Pathology, Karadeniz Technical University School of Medicine, Trabzon, Turkey
| | - Aydanur Ekici
- Department of Chest Diseases, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - Nurkan Aksoy
- Clinic of Biochemistry, Yenimahalle State Hospital, Ankara, Turkey
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17
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Abstract
As the prevalence and impact of lung diseases continue to increase worldwide, new therapeutic strategies are desperately needed. Advances in lung-regenerative medicine, a broad field encompassing stem cells, cell-based therapies, and a range of bioengineering approaches, offer new insights into and new techniques for studying lung physiology and pathophysiology. This provides a platform for the development of novel therapeutic approaches. Applicability to chronic obstructive pulmonary disease of recent advances and applications in cell-based therapies, predominantly those with mesenchymal stromal cell-based approaches, and bioengineering approaches for lung diseases are reviewed.
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18
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Yonker LM, Kinane TB. Diagnostic and clinical course of pulmonary interstitial glycogenosis: The tip of the iceberg. Pediatr Pulmonol 2018; 53:1659-1661. [PMID: 30259700 DOI: 10.1002/ppul.24167] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 08/10/2018] [Indexed: 01/22/2023]
Abstract
"Pulmonary Interstitial Glycogenosis: Diagnostic Evaluation and Clinical Course," written by Liptzin et al is a timely and insightful phenotypic summary of a rare pediatric interstitial lung disease. Twenty-four infants with biopsy-proven pulmonary interstitial glycogenosis (PIG) were reviewed at their center. Genetic analysis, bronchoscopy results, imaging, biopsy, and cardiology findings were described, and treatment decision and clinical outcomes were discussed.
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Affiliation(s)
- Lael M Yonker
- Division of Pediatric Pulmonary, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts
| | - T Bernard Kinane
- Division of Pediatric Pulmonary, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts
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19
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Coppolino I, Ruggeri P, Nucera F, Cannavò MF, Adcock I, Girbino G, Caramori G. Role of Stem Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Pulmonary Emphysema. COPD 2018; 15:536-556. [DOI: 10.1080/15412555.2018.1536116] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Irene Coppolino
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Paolo Ruggeri
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Francesco Nucera
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Mario Francesco Cannavò
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Ian Adcock
- Airways Disease Section, National Heart and Lung Institute, Royal Brompton Hospital Biomedical Research Unit, Imperial College, London, UK
| | - Giuseppe Girbino
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
| | - Gaetano Caramori
- Dipartimento di Scienze Biomediche, Unità Operativa Complessa di Pneumologia, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università degli Studi di Messina, Messina, Italy
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20
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Kokturk N, Yıldırım F, Gülhan PY, Oh YM. Stem cell therapy in chronic obstructive pulmonary disease. How far is it to the clinic? AMERICAN JOURNAL OF STEM CELLS 2018; 7:56-71. [PMID: 30245915 PMCID: PMC6146161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 07/01/2018] [Indexed: 06/08/2023]
Abstract
Chronic obstructive pulmonary disease (COPD) is a respiratory disease that has a major impact worldwide. The currently-available drugs mainly focus on relieving the symptoms of COPD patients. However, in the latter stages of the disease, the airways become largely obstructed and lung parenchyma becomes destructed due to underlying inflammation. The inappropriate repair of lung tissue after injury may contribute to the development of disease. Novel regenerative therapeutic approaches have been investigated with the aim of repairing or replacing the injured functional structures of the respiratory system. Endogenous and exogenous sources of stem cells are available for the treatment of many diseases. Stem cell therapy is newly introduced to the field of COPD. Currently the research is in its infancy; however, the field is profoundly growing. Previous studies suggest that cell-based therapies and novel bioengineering approaches may be potential therapeutic strategies for lung repair and remodelling. In this paper, we review the current evidence of stem cell therapy in COPD.
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Affiliation(s)
- Nurdan Kokturk
- Department of Pulmonary and Critical Care Medicine, School of Medicine, Gazi UniversityAnkara, Turkey
| | - Fatma Yıldırım
- Dışkapı Yıldırım Beyazıt Research and Education Hospital, Pulmonary & Critical Care MedicineAnkara, Turkey
| | - Pınar Yıldız Gülhan
- Department of Pulmonary Medicine, Düzce University Faculty of MedicineDüzce, Turkey
| | - Yeon Mok Oh
- Department of Pulmonary and Critical Care Medicine and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of MedicineSeoul, South Korea
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21
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Al-Rubaie A, Wise AF, Sozo F, De Matteo R, Samuel CS, Harding R, Ricardo SD. The therapeutic effect of mesenchymal stem cells on pulmonary myeloid cells following neonatal hyperoxic lung injury in mice. Respir Res 2018; 19:114. [PMID: 29884181 PMCID: PMC5994120 DOI: 10.1186/s12931-018-0816-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 05/21/2018] [Indexed: 02/03/2023] Open
Abstract
Background Exposure to high levels of oxygen (hyperoxia) after birth leads to lung injury. Our aims were to investigate the modulation of myeloid cell sub-populations and the reduction of fibrosis in the lungs following administration of human mesenchymal stem cells (hMSC) to neonatal mice exposed to hyperoxia. Method Newborn mice were exposed to 90% O2 (hyperoxia) or 21% O2 (normoxia) from postnatal days 0–4. A sub-group of hyperoxia mice were injected intratracheally with 2.5X105 hMSCs. Using flow cytometry we assessed pulmonary immune cells at postnatal days 0, 4, 7 and 14. The following markers were chosen to identify these cells: CD45+ (leukocytes), Ly6C+Ly6G+ (granulocytes), CD11b+CD11c+ (macrophages); macrophage polarisation was assessed by F4/80 and CD206 expression. hMSCs expressing enhanced green fluorescent protein (eGFP) and firefly luciferase (fluc) were administered via the trachea at day 4. Lung macrophages in all groups were profiled using next generation sequencing (NGS) to assess alterations in macrophage phenotype. Pulmonary collagen deposition and morphometry were assessed at days 14 and 56 respectively. Results At day 4, hyperoxia increased the number of pulmonary Ly6C+Ly6G+ granulocytes and F4/80lowCD206low macrophages but decreased F4/80highCD206high macrophages. At days 7 and 14, hyperoxia increased numbers of CD45+ leukocytes, CD11b+CD11c+ alveolar macrophages and F4/80lowCD206low macrophages but decreased F4/80highCD206high macrophages. hMSCs administration ameliorated these effects of hyperoxia, notably reducing numbers of CD11b+CD11c+ and F4/80lowCD206low macrophages; in contrast, F4/80highCD206high macrophages were increased. Genes characteristic of anti-inflammatory ‘M2’ macrophages (Arg1, Stat6, Retnla, Mrc1, Il27ra, Chil3, and Il12b) were up-regulated, and pro-inflammatory ‘M1’ macrophages (Cd86, Stat1, Socs3, Slamf1, Tnf, Fcgr1, Il12b, Il6, Il1b, and Il27ra) were downregulated in isolated lung macrophages from hyperoxia-exposed mice administered hMSCs, compared to mice without hMSCs. Hydroxyproline assay at day 14 showed that the 2-fold increase in lung collagen following hyperoxia was reduced to control levels in mice administered hMSCs. By day 56 (early adulthood), hMSC administration had attenuated structural changes in hyperoxia-exposed lungs. Conclusions Our findings suggest that hMSCs reduce neonatal lung injury caused by hyperoxia by modulation of macrophage phenotype. Not only did our cell-based therapy using hMSC induce structural repair, it limited the progression of pulmonary fibrosis. Electronic supplementary material The online version of this article (10.1186/s12931-018-0816-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ali Al-Rubaie
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Andrea F Wise
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Foula Sozo
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Robert De Matteo
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Chrishan S Samuel
- Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, Australia
| | - Richard Harding
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
| | - Sharon D Ricardo
- Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
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22
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Broekman W, Khedoe PPSJ, Schepers K, Roelofs H, Stolk J, Hiemstra PS. Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease? Thorax 2018; 73:565-574. [PMID: 29653970 PMCID: PMC5969341 DOI: 10.1136/thoraxjnl-2017-210672] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 03/18/2018] [Accepted: 03/26/2018] [Indexed: 12/11/2022]
Abstract
COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research.
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Affiliation(s)
- Winifred Broekman
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Padmini P S J Khedoe
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Koen Schepers
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Helene Roelofs
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan Stolk
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
| | - Pieter S Hiemstra
- Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
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Lung Mesenchymal Stem Cells Ameliorate Elastase-Induced Damage in an Animal Model of Emphysema. Stem Cells Int 2018; 2018:9492038. [PMID: 29731780 PMCID: PMC5872595 DOI: 10.1155/2018/9492038] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/15/2017] [Accepted: 12/21/2017] [Indexed: 12/28/2022] Open
Abstract
Pulmonary emphysema is a respiratory condition characterized by alveolar destruction that leads to airflow limitation and reduced lung function. Although with extensive research, the pathophysiology of emphysema is poorly understood and effective treatments are still missing. Evidence suggests that mesenchymal stem cells (MSCs) possess the ability to engraft the injured tissues and induce repair via a paracrine effect. Thus, the aim of this study was to test the effects of the intratracheal administration of lung-derived mouse MSCs in a model of elastase-induced emphysema. Pulmonary function (static lung compliance) showed an increased stiffness induced by elastase, while morphometric findings (mean linear intercept and tissue/alveolar area) confirmed the severity of alveolar disruption. Contrarily, MSC administration partially restored lung elasticity and alveolar architecture. In the absence of evidence that MSCs acquired epithelial phenotype, we detected an increased proliferative activity of aquaporin 5- and surfactant protein C-positive lung cells, suggesting MSC-driven paracrine mechanisms. The data indicate the mediation of hepatocyte growth factor in amplifying MSC-driven tissue response after injury. Our study shed light on supportive properties of lung-derived MSCs, although the full identification of mechanisms orchestrated by MSCs and responsible for epithelial repair after injury is a critical aspect yet to be achieved.
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Chhetri JK, de Souto Barreto P, Fougère B, Rolland Y, Vellas B, Cesari M. Chronic inflammation and sarcopenia: A regenerative cell therapy perspective. Exp Gerontol 2018; 103:115-123. [DOI: 10.1016/j.exger.2017.12.023] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 12/20/2017] [Accepted: 12/27/2017] [Indexed: 01/06/2023]
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Janczewski AM, Wojtkiewicz J, Malinowska E, Doboszyńska A. Can Youthful Mesenchymal Stem Cells from Wharton's Jelly Bring a Breath of Fresh Air for COPD? Int J Mol Sci 2017; 18:ijms18112449. [PMID: 29156550 PMCID: PMC5713416 DOI: 10.3390/ijms18112449] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 11/13/2017] [Accepted: 11/14/2017] [Indexed: 12/13/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a major global cause of morbidity and mortality, projected to become the 3rd cause of disease mortality worldwide by 2020. COPD is characterized by persistent and not fully reversible airflow limitation that is usually progressive and is associated with an abnormal chronic inflammatory response of the lung to noxious agents including cigarette smoke. Currently available therapeutic strategies aim to ease COPD symptoms but cannot prevent its progress or regenerate physiological lung structure or function. The urgently needed new approaches for the treatment of COPD include stem cell therapies among which transplantation of mesenchymal stem cells derived from Wharton’s jelly (WJ-MSCs) emerges as a promising therapeutic strategy because of the unique properties of these cells. The present review discusses the main biological properties of WJ-MSCs pertinent to their potential application for the treatment of COPD in the context of COPD pathomechanisms with emphasis on chronic immune inflammatory processes that play key roles in the development and progression of COPD.
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Affiliation(s)
- Andrzej M Janczewski
- Department of Pulmonology, Faculty of Heath Sciences, University of Warmia and Mazury in Olsztyn, Jagiellońska 78, 10-357 Olsztyn, Poland.
| | - Joanna Wojtkiewicz
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082 Olsztyn, Poland.
- Laboratory for Regenerative Medicine, Faculty of Medicine, University of Warmia and Mazury in Olsztyn, Warszawska 30, 10-082 Olsztyn, Poland.
- Foundation for the Nerve Cells Regeneration, Warszawska 30, 10-082 Olsztyn, Poland.
| | - Ewa Malinowska
- Department of Pulmonology, Faculty of Heath Sciences, University of Warmia and Mazury in Olsztyn, Jagiellońska 78, 10-357 Olsztyn, Poland.
| | - Anna Doboszyńska
- Department of Pulmonology, Faculty of Heath Sciences, University of Warmia and Mazury in Olsztyn, Jagiellońska 78, 10-357 Olsztyn, Poland.
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Li F, Han F, Li H, Zhang J, Qiao X, Shi J, Yang L, Dong J, Luo M, Wei J, Liu X. Human placental mesenchymal stem cells of fetal origins-alleviated inflammation and fibrosis by attenuating MyD88 signaling in bleomycin-induced pulmonary fibrosis mice. Mol Immunol 2017; 90:11-21. [PMID: 28662409 DOI: 10.1016/j.molimm.2017.06.032] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Revised: 05/16/2017] [Accepted: 06/18/2017] [Indexed: 01/20/2023]
Abstract
Pulmonary fibrosis is a progressive lung disease that its pathogenic mechanism currently is incompletely understood. Toll-like receptor (TLR) signaling has recently been identified as a regulator of inflammation and pulmonary fibrosis. In addition, mesenchymal stem cells (MSCs) of different origins offer a great promise in treatment of idiopathic pulmonary fibrosis (IPF). However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in MyD88-deficient mice using human placental MSCs of fetal origins (hfPMSCs). The results showed an alleviated pulmonary inflammation and fibrosis in myeloid differentiation primary response gene 88 (MyD88)-deficient mice treated with bleomycin (BLM), accompanied with a reduced TGF-β signaling and production of pro-fibrotic cytokines, including TNF-α, IL-1β. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of MyD88 and TGF-β signaling cascades. Of interest, enforced expression and inhibition of MyD88 protein resulted in an enhanced and a reduced TGF-β signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-β1 showed a marginally inhibitory effect on MyD88 signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary fibrosis in mice, along with a reduced hydroxyproline (HYP) deposition, MyD88 and TGF-β signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of MyD88/TGF-β signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary fibrosis.
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Affiliation(s)
- Feng Li
- Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China; Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Fei Han
- Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Hui Li
- Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Jia Zhang
- Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Xia Qiao
- Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Juan Shi
- Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Li Yang
- The Center of Experimental Animals, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Jianda Dong
- Department of Pathology, Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Meihui Luo
- Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Jun Wei
- Center of Laboratory Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China; Department of Laboratory Medicine, College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China; Institute of Human Stem Cell Research, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China
| | - Xiaoming Liu
- College of Life Science, Ningxia University, Yinchuan, Ningxia 750021, China.
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