|
1
|
Wan R, Liu Y, Yan J, Lin J. Cell therapy: A beacon of hope in the battle against pulmonary fibrosis. FASEB J 2025; 39:e70356. [PMID: 39873972 DOI: 10.1096/fj.202402790r] [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: 11/10/2024] [Revised: 12/28/2024] [Accepted: 01/15/2025] [Indexed: 01/30/2025]
Abstract
Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease characterized by abnormal activation of myofibroblasts and pathological remodeling of the extracellular matrix, with a poor prognosis and limited treatment options. Lung transplantation is currently the only approach that can extend the life expectancy of patients; however, its applicability is severely restricted due to donor shortages and patient-specific limitations. Therefore, the search for novel therapeutic strategies is imperative. In recent years, stem cells have shown great promise in the field of regenerative medicine due to their self-renewal capacity and multidirectional differentiation potential, and a growing body of literature supports the efficacy of stem cell therapy in PF treatment. This paper systematically summarizes the research progress of various stem cell types in the treatment of PF. Furthermore, it discusses the primary methods and clinical outcomes of stem cell therapy in PF, based on both preclinical and clinical data. Finally, the current challenges and key factors to consider in stem cell therapy for PF are objectively analyzed, and future directions for improving this therapy are proposed, providing new insights and references for the clinical treatment of PF patients.
Collapse
Affiliation(s)
- Ruyan Wan
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Yanli Liu
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
| | - Jingwen Yan
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China
| | - Juntang Lin
- Stem Cell and Biotherapy Technology Research Center, School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Biomedical Engineering, Xinxiang Medical University, Xinxiang, China
| |
Collapse
|
|
2
|
Diwan R, Bhatt HN, Beaven E, Nurunnabi M. Emerging delivery approaches for targeted pulmonary fibrosis treatment. Adv Drug Deliv Rev 2024; 204:115147. [PMID: 38065244 PMCID: PMC10787600 DOI: 10.1016/j.addr.2023.115147] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 01/01/2024]
Abstract
Pulmonary fibrosis (PF) is a progressive, and life-threatening interstitial lung disease which causes scarring in the lung parenchyma and thereby affects architecture and functioning of lung. It is an irreversible damage to lung functioning which is related to epithelial cell injury, immense accumulation of immune cells and inflammatory cytokines, and irregular recruitment of extracellular matrix. The inflammatory cytokines trigger the differentiation of fibroblasts into activated fibroblasts, also known as myofibroblasts, which further increase the production and deposition of collagen at the injury sites in the lung. Despite the significant morbidity and mortality associated with PF, there is no available treatment that efficiently and effectively treats the disease by reversing their underlying pathologies. In recent years, many therapeutic regimens, for instance, rho kinase inhibitors, Smad signaling pathway inhibitors, p38, BCL-xL/ BCL-2 and JNK pathway inhibitors, have been found to be potent and effective in treating PF, in preclinical stages. However, due to non-selectivity and non-specificity, the therapeutic molecules also result in toxicity mediated severe side effects. Hence, this review demonstrates recent advances on PF pathology, mechanism and targets related to PF, development of various drug delivery systems based on small molecules, RNAs, oligonucleotides, peptides, antibodies, exosomes, and stem cells for the treatment of PF and the progress of various therapeutic treatments in clinical trials to advance PF treatment.
Collapse
Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Himanshu N Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Elfa Beaven
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX 79902, United States; Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX 79968, United States; The Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX 79968, United States.
| |
Collapse
|
|
3
|
Guo Z, Zhang Y, Yan F. Potential of Mesenchymal Stem Cell-Based Therapies for Pulmonary Fibrosis. DNA Cell Biol 2022; 41:951-965. [DOI: 10.1089/dna.2022.0327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Zhihou Guo
- Stem Cell Lab, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yaping Zhang
- Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Furong Yan
- Center for Molecular Diagnosis and Therapy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| |
Collapse
|
|
4
|
Abstract
Pulmonary fibrosis (PF) is a chronic and relentlessly progressive interstitial lung disease in which the accumulation of fibroblasts and extracellular matrix (ECM) induces the destruction of normal alveolar structures, ultimately leading to respiratory failure. Patients with advanced PF are unable to perform physical labor and often have concomitant cough and dyspnea, which markedly impair their quality of life. However, there is a paucity of available pharmacological therapies, and to date, lung transplantation remains the only possible treatment for patients suffering from end-stage PF; moreover, the complexity of transplantation surgery and the paucity of donors greatly restrict the application of this treatment. Therefore, there is a pressing need for alternative therapeutic strategies for this complex disease. Due to their capacity for pluripotency and paracrine actions, stem cells are promising therapeutic agents for the treatment of interstitial lung disease, and an extensive body of literature supports the therapeutic efficacy of stem cells in lung fibrosis. Although stem cell transplantation may play an important role in the treatment of PF, some key issues, such as safety and therapeutic efficacy, remain to be resolved. In this review, we summarize recent preclinical and clinical studies on the stem cell-mediated regeneration of fibrotic lungs and present an analysis of concerning issues related to stem cell therapy to guide therapeutic development for this complex disease.
Collapse
|
|
5
|
Brown SAW, Iancu-Rubin C, Aboelela A, Abrahams A, Burke E, Drummond T, Grossman F, Itescu S, Lagdameo J, Lin JY, Mark A, Levine JE, Osman K. Mesenchymal Stromal Cell Therapy for Acute Respiratory Distress Syndrome due to COVID-19. Cytotherapy 2022; 24:835-840. [PMID: 35649958 PMCID: PMC8995321 DOI: 10.1016/j.jcyt.2022.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 02/01/2022] [Accepted: 03/17/2022] [Indexed: 11/26/2022]
Abstract
Background aims The acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications. Methods Patients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48–120 h apart. Results Remestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59–100%) patients were extubated, nine (82%, 95% CI, 48–97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2–52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34–100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion. Conclusions The authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.
Collapse
|
|
6
|
Namba F. Mesenchymal stem cells for the prevention of bronchopulmonary dysplasia. Pediatr Int 2019; 61:945-950. [PMID: 31487104 DOI: 10.1111/ped.14001] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 07/06/2019] [Accepted: 08/29/2019] [Indexed: 12/19/2022]
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants who have been treated with supplemental oxygen and mechanical ventilation. Despite major advances in perinatal and neonatal medicine, limited progress has been made in reducing BPD rates. The use of mesenchymal stem cells (MSC) is a promising and innovative therapy for several diseases because they are easy to extract and they have low immunogenicity, anti-inflammatory properties, and regenerative ability. According to several pre-clinical studies that have used BPD animal models, one mechanism of action for MSC in BPD is mainly due to the paracrine effects of MSC-derived humoral factors, such as interleukin (IL)-6, IL-8, vascular endothelial growth factor, collagen, and elastin, rather than the multilineage and regenerative capacities of MSC. Cell-free preparations derived from MSC, including conditioned media and exosomes, remain a pre-clinical technology despite their great clinical potential. A first-in-human clinical trial of MSC treatment for BPD was performed as a phase I dose-escalation trial using umbilical cord blood-derived MSC. That trial demonstrated the short- and long-term safety and feasibility of MSC, given that significantly reduced inflammatory marker expression was observed in tracheal aspirates. As of recently, several clinical trials of MSC use for BPD are ongoing or are planned in some countries to investigate the efficacy of MSC in the prevention or treatment of BPD in premature infants. Many clinicians are currently awaiting the results from these trials so that MSC can be used clinically for human BPD.
Collapse
Affiliation(s)
- Fumihiko Namba
- Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
| |
Collapse
|
|
7
|
CXCR4-Overexpressing Umbilical Cord Mesenchymal Stem Cells Enhance Protection against Radiation-Induced Lung Injury. Stem Cells Int 2019; 2019:2457082. [PMID: 30867667 PMCID: PMC6379846 DOI: 10.1155/2019/2457082] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/31/2018] [Accepted: 11/07/2018] [Indexed: 12/13/2022] Open
Abstract
Less quantity of transplanted mesenchymal stem cells (MSCs) influences the therapeutic effects on radiation-induced lung injury (RILI). Previous studies have demonstrated that MSCs overexpressing Chemokine (C-X-C motif) receptor 4 (CXCR4) could increase the quantity of transplanted cells to local tissues. In the present study, we conducted overexpressing CXCR4 human umbilical cord mesenchymal stem cell (HUMSC) therapy for RILI. C57BL mice received single dose of thoracic irradiation with 13 Gy of X-rays and then were administered saline, control HUMSCs, or CXCR4-overexpressing HUMSCs via tail vein. Transfection with CXCR4 enhanced the quantity of transplanted HUMSCs in the radiation-induced injured lung tissues. CXCR4-overexpressing HUMSCs not only improved histopathological changes but also decreased the radiation-induced expression of SDF-1, TGF-β1, α-SMA, and collagen I and inhibited the radiation-induced decreased expression of E-cadherin. Transplanted CXCR4-overexpressing HUMSCs also could express pro-SP-C, indicated adopting the feature of ATII. These finding suggests that CXCR4-overexpressing HUMSCs enhance the protection against RILI and may be a promising strategy for RILI treatment.
Collapse
|
|
8
|
Su X, Yang L, Yin Y, Huang J, Qiao F, Fang Y, Yu L, Wang Y, Zhou K, Wang J. Bone marrow mesenchymal stem cells tune the differentiation of myeloid-derived suppressor cells in bleomycin-induced lung injury. Stem Cell Res Ther 2018; 9:253. [PMID: 30257700 PMCID: PMC6158827 DOI: 10.1186/s13287-018-0983-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 08/13/2018] [Accepted: 08/15/2018] [Indexed: 01/28/2023] Open
Abstract
Background Bone marrow mesenchymal stem cells (BMSC) transfer has been attempted as a therapeutic strategy in experimental lung injury and fibrosis. Reduction of neutrophilic infiltration is one of the mechanisms involved in this effect. However, the mechanisms by which BMSC modulate neutrophil remains unknown. Methods and results Exposure of mice to bleomycin (BLM) resulted in significant accumulation of cells that express neutrophilic markers Gr-1HighCD11b+Ly-6GHighF4/80―CD115―CD49d―. These cells lacked immunosuppressive activity and could not be defined as myeloid-derived suppressor cells (MDSC). When BMSC were administrated to BLM-treated mice, they tuned the differentiation of Gr-1HighCD11b+ toward Gr-1LowCD11b+ cells. Gr-1LowCD11b+ cells exhibited unsegmented nuclei and expressed F4/80, Ly-6C, CD49d, and CD115 markers. These cells had potent immunosuppressive activity and thus could be defined as monocytic MDSC. As a result of such immunoregulation, BMSC mediated a decrease of pro-inflammatory products and amelioration of lung injury in BLM-treated mice. Further study using antibody array showed increased expression of macrophage colony-stimulating factor (M-CSF) in BMSC-treated mice. Accumulation of Gr-1LowCD11b+ cells in BMSC-treated mice was abrogated in M-CSF neutralizing mice. The beneficial effect of BMSC was independent of the ability of the cells to engraft in lung and in vitro coculture study of BMSC with Gr-1+CD11b+ cells showed that the induction of Gr-1LowCD11b+ cells by BMSC was independent of cell-cell contact. Conclusions These results document the generation of Gr-1HighCD11b+ cells in BLM-treated mice, and suggest that BMSC tune the differentiation of Gr-1HighCD11b+ toward Gr-1LowCD11b+ cells and therefore inhibit the progression of BLM-induced lung injury. Electronic supplementary material The online version of this article (10.1186/s13287-018-0983-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- XiaoSan Su
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, People's Republic of China
| | - Liu Yang
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, People's Republic of China
| | - YanFeng Yin
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, People's Republic of China
| | - Jie Huang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan, 650032, People's Republic of China
| | - Fei Qiao
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan, 650032, People's Republic of China
| | - Yu Fang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan, 650032, People's Republic of China
| | - Lu Yu
- Department of Pathology, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, People's Republic of China
| | - YinYin Wang
- Biomedical Research Center, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, People's Republic of China
| | - KaiHua Zhou
- Department of Respiratory Diseases, Affiliated Calmette Hospital of Kunming Medical University, 504 Qing Nian Road, Kunming, Yunnan, 650011, People's Republic of China
| | - Jun Wang
- Department of Anesthesiology, First Affiliated Hospital of Kunming Medical University, 295 Xi Chang Road, Kunming, Yunnan, 650032, People's Republic of China.
| |
Collapse
|
|
9
|
Beers MF, Moodley Y. When Is an Alveolar Type 2 Cell an Alveolar Type 2 Cell? A Conundrum for Lung Stem Cell Biology and Regenerative Medicine. Am J Respir Cell Mol Biol 2017; 57:18-27. [PMID: 28326803 DOI: 10.1165/rcmb.2016-0426ps] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Generating mature, differentiated, adult lung cells from pluripotent cells, such as induced pluripotent stem cells and embryonic stem cells, offers the hope of both generating disease-specific in vitro models and creating definitive and personalized therapies for a host of debilitating lung parenchymal and airway diseases. With the goal of advancing lung-regenerative medicine, several groups have developed and reported on protocols using defined media, coculture with mesenchymal components, or sequential treatments mimicking lung development, to obtain distal lung epithelial cells from stem cell precursors. However, there remains significant controversy about the degree of differentiation of these cells compared with their primary counterparts, coupled with a lack of consistency or uniformity in assessing the resultant phenotypes. Given the inevitable, exponential expansion of these approaches and the probable, but yet-to-emerge second and higher generation techniques to create such assets, we were prompted to pose the question, what makes a lung epithelial cell a lung epithelial cell? More specifically for this Perspective, we also posed the question, what are the minimum features that constitute an alveolar type (AT) 2 epithelial cell? In addressing this, we summarize a body of work spanning nearly five decades, amassed by a series of "lung epithelial cell biology pioneers," which carefully describes well characterized molecular, functional, and morphological features critical for discriminately assessing an AT2 phenotype. Armed with this, we propose a series of core criteria to assist the field in confirming that cells obtained following a differentiation protocol are indeed mature and functional AT2 epithelial cells.
Collapse
Affiliation(s)
- Michael F Beers
- 1 Lung Epithelial Biology Laboratories, Penn Center for Pulmonary Biology, Pulmonary and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and
| | - Yuben Moodley
- 2 University of Western Australia, Harry Perkins Research Institute, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| |
Collapse
|
|
10
|
Maria OM, Maria AM, Ybarra N, Jeyaseelan K, Lee S, Perez J, Shalaby MY, Lehnert S, Faria S, Serban M, Seuntjens J, El Naqa I. Mesenchymal Stem Cells Adopt Lung Cell Phenotype in Normal and Radiation-induced Lung Injury Conditions. Appl Immunohistochem Mol Morphol 2016. [PMID: 26200842 DOI: 10.1097/pai.0000000000000180] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Lung tissue exposure to ionizing irradiation can invariably occur during the treatment of a variety of cancers leading to increased risk of radiation-induced lung disease (RILD). Mesenchymal stem cells (MSCs) possess the potential to differentiate into epithelial cells. However, cell culture methods of primary type II pneumocytes are slow and cannot provide a sufficient number of cells to regenerate damaged lungs. Moreover, effects of ablative radiation doses on the ability of MSCs to differentiate in vitro into lung cells have not been investigated yet. Therefore, an in vitro coculture system was used, where MSCs were physically separated from dissociated lung tissue obtained from either healthy or high ablative doses of 16 or 20 Gy whole thorax irradiated rats. Around 10±5% and 20±3% of cocultured MSCs demonstrated a change into lung-specific Clara and type II pneumocyte cells when MSCs were cocultured with healthy lung tissue. Interestingly, in cocultures with irradiated lung biopsies, the percentage of MSCs changed into Clara and type II pneumocytes cells increased to 40±7% and 50±6% at 16 Gy irradiation dose and 30±5% and 40±8% at 20 Gy irradiation dose, respectively. These data suggest that MSCs to lung cell differentiation is possible without cell fusion. In addition, 16 and 20 Gy whole thorax irradiation doses that can cause varying levels of RILD, induced different percentages of MSCs to adopt lung cell phenotype compared with healthy lung tissue, providing encouraging outlook for RILD therapeutic intervention for ablative radiotherapy prescriptions.
Collapse
Affiliation(s)
- Ola M Maria
- *Medical Physics Unit, Department of Oncology, Radiation Oncology Division, McGill University, Montreal General Hospital ‡Department of Oncology, Radiation Oncology Division, McGill University Health Centre ∥International Baccalaureate, Marymount Academy, Montreal, QC, Canada †Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura §Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Hegab AE, Betsuyaku T. Lung Stem Cells and Their Use for Patient Care: Are We There Yet? ACTA ACUST UNITED AC 2016. [DOI: 10.1007/978-3-319-33270-3_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
|
|
12
|
Effect of irradiation/bone marrow transplantation on alveolar epithelial type II cells is aggravated in surfactant protein D deficient mice. Histochem Cell Biol 2016; 147:49-61. [PMID: 27565967 DOI: 10.1007/s00418-016-1479-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/16/2016] [Indexed: 10/21/2022]
Abstract
Irradiation followed by bone marrow transplantation (BM-Tx) is a frequent therapeutic intervention causing pathology to the lung. Although alveolar epithelial type II (AE2) cells are essential for lung function and are damaged by irradiation, the long-term consequences of irradiation and BM-Tx are not well characterized. In addition, it is unknown whether surfactant protein D (SP-D) influences the response of AE2 cells to the injurious events. Therefore, wildtype (WT) and SP-D-/- mice were subjected to a myeloablative whole body irradiation dose of 8 Gy and subsequent BM-Tx and compared with age- and sex-matched untreated controls. AE2 cell changes were investigated quantitatively by design-based stereology. Compared with WT, untreated SP-D-/- mice showed a higher number of larger sized AE2 cells and a greater amount of surfactant-storing lamellar bodies. Irradiation and BM-Tx induced hyperplasia and hypertrophy in WT and SP-D-/- mice as well as the formation of giant lamellar bodies. The experimentally induced alterations were more severe in the SP-D-/- than in the WT mice, particularly with respect to the surfactant-storing lamellar bodies which were sometimes extremely enlarged in SP-D-/- mice. In conclusion, irradiation and BM-Tx have profound long-term effects on AE2 cells and their lamellar bodies. These data may explain some of the clinical pulmonary consequences of this procedure. The data should also be taken into account when BM-Tx is used as an experimental procedure to investigate the impact of bone marrow-derived cells for the phenotype of a specific genotype in the mouse.
Collapse
|
|
13
|
Bohlin K. Cell-based strategies to reconstitute vital functions in preterm infants with organ failure. Best Pract Res Clin Obstet Gynaecol 2016; 31:99-111. [DOI: 10.1016/j.bpobgyn.2015.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 08/31/2015] [Indexed: 12/14/2022]
|
|
14
|
Trzil JE, Masseau I, Webb TL, Chang CH, Dodam JR, Cohn LA, Liu H, Quimby JM, Dow SW, Reinero CR. Long-term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma. Clin Exp Allergy 2015; 44:1546-57. [PMID: 25220646 DOI: 10.1111/cea.12411] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Revised: 07/16/2014] [Accepted: 08/12/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodelling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model. OBJECTIVE To document effects of allogeneic, adipose-derived MSCs on airway inflammation, AHR, and remodelling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma. METHODS Cats with chronic, experimentally induced asthma received six intravenous infusions of MSCs (0.36-2.5 × 10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for 1 year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia, pulmonary mechanics and clinical scoring to assess AHR, and thoracic computed tomographic (CT) scans to assess structural changes (airway remodelling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen-specific IgE, cellular IL-10 production, and allergen-specific lymphocyte proliferation were performed. RESULTS There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC-treated animals compared to placebo-treated cats at month 8 of the study (LA P = 0.0311; BWT P = 0.0489). No differences were noted between groups in the immunologic assays. CONCLUSIONS AND CLINICAL RELEVANCE When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodelling by month 8, although the effect was not sustained at month 12. Further study of MSC therapy including repeated MSC administration is warranted to assess impact on remodelling in chronic asthma.
Collapse
Affiliation(s)
- J E Trzil
- Comparative Internal Medicine Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA; Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Fujita M. New therapies for chronic obstructive pulmonary disease, lung regeneration. World J Respirol 2015; 5:34-39. [DOI: 10.5320/wjr.v5.i1.34] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 12/15/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow limitations that are not fully reversible and is a major cause of chronic morbidity and mortality worldwide. Although there has been extensive research examining the molecular mechanisms underlying the development of COPD, there is no proven clinically effective treatment for promoting recovery from established COPD. At present, regeneration is the only hope for a cure in patients with COPD. In this article, we review current treatments for COPD, focusing particularly on recent advances in lung regeneration based on two major approaches: regeneration-promoting agents and cell therapy. Retinoic acids are the major focus among regeneration-promoting agents, while mesenchymal stem cells are the main topic in the field of cell-based therapy. This article aims to provide valuable information for developing new therapies for COPD.
Collapse
|
|
16
|
Sdrimas K, Kourembanas S. MSC microvesicles for the treatment of lung disease: a new paradigm for cell-free therapy. Antioxid Redox Signal 2014; 21:1905-15. [PMID: 24382303 PMCID: PMC4202925 DOI: 10.1089/ars.2013.5784] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of infancy, is a major complication of preterm birth that, despite improvements in neonatal respiratory support and perinatal care, remains an important cause of morbidity and mortality, often with severe adverse neurodevelopmental sequelae. Even with major advances in our understanding of the pathogenesis of this disease, BPD remains essentially without adequate treatment. RECENT ADVANCES Cell-based therapies arose as a promising treatment for acute and chronic lung injury in many experimental models of disease. Currently, more than 3000 human clinical trials employing cell therapy for the treatment of diverse diseases, including cardiac, neurologic, immune, and respiratory conditions, are ongoing or completed. Among the treatments, mesenchymal stem cells (MSCs) are the most studied and have been extensively tested in experimental models of BPD, pulmonary hypertension, pulmonary fibrosis, and acute lung injury. CRITICAL ISSUES Despite the promising potential, MSC therapy for human lung disease still remains at an experimental stage and optimal transplantation conditions need to be determined. Although the mechanism of MSC action can be manifold, accumulating evidence suggests a predominant paracrine, immunomodulatory, and cytoprotective effect. FUTURE DIRECTIONS The current review summarizes the effect of MSC treatment in models of lung injury, including BPD, and focuses on the MSC secretome and, specifically, MSC-derived microvesicles as potential key mediators of therapeutic action that can be the focus of future therapies.
Collapse
Affiliation(s)
- Konstantinos Sdrimas
- 1 Division of Newborn Medicine, Boston Children's Hospital , Boston, Massachusetts
| | | |
Collapse
|
|
17
|
Zhou Q, Ye X, Sun R, Matsumoto Y, Moriyama M, Asano Y, Ajioka Y, Saijo Y. Differentiation of mouse induced pluripotent stem cells into alveolar epithelial cells in vitro for use in vivo. Stem Cells Transl Med 2014; 3:675-85. [PMID: 24763685 DOI: 10.5966/sctm.2013-0142] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Alveolar epithelial cells (AECs) differentiated from induced pluripotent stem cells (iPSCs) represent new opportunities in lung tissue engineering and cell therapy. In this study, we modified a two-step protocol for embryonic stem cells that resulted in a yield of ∼9% surfactant protein C (SPC)(+) alveolar epithelial type II (AEC II) cells from mouse iPSCs in a 12-day period. The differentiated iPSCs showed morphological characteristics similar to those of AEC II cells. When differentiated iPSCs were seeded and cultured in a decellularized mouse lung scaffold, the cells reformed an alveolar structure and expressed SPC or T1α protein (markers of AEC II or AEC I cells, respectively). Finally, the differentiated iPSCs were instilled intratracheally into a bleomycin-induced mouse acute lung injury model. The transplanted cells integrated into the lung alveolar structure and expressed SPC and T1α. Significantly reduced lung inflammation and decreased collagen deposition were observed following differentiated iPSC transplantation. In conclusion, we report a simple and rapid protocol for in vitro differentiation of mouse iPSCs into AECs. Differentiated iPSCs show potential for regenerating three-dimensional alveolar lung structure and can be used to abrogate lung injury.
Collapse
Affiliation(s)
- Qiliang Zhou
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Xulu Ye
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Ruowen Sun
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yoshifumi Matsumoto
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Masato Moriyama
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yoshiya Asano
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yoichi Ajioka
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yasuo Saijo
- Department of Medical Oncology and Division of Molecular and Diagnostic Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Department of Pediatric Hematology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China; Department of Neuroanatomy, Cell Biology, and Histology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| |
Collapse
|
|
18
|
Hematopoietic and mesenchymal stem cells for the treatment of chronic respiratory diseases: role of plasticity and heterogeneity. ScientificWorldJournal 2014; 2014:859817. [PMID: 24563632 PMCID: PMC3916026 DOI: 10.1155/2014/859817] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 10/20/2013] [Indexed: 12/21/2022] Open
Abstract
Chronic lung diseases, such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) are incurable and represent a very high social burden. Stem cell-based treatment may represent a hope for the cure of these diseases. In this paper, we revise the overall knowledge about the plasticity and engraftment of exogenous marrow-derived stem cells into the lung, as well as their usefulness in lung repair and therapy of chronic lung diseases. The lung is easily accessible and the pathophysiology of these diseases is characterized by injury, inflammation, and eventually by remodeling of the airways. Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal (stem) cells (MSCs), encompass a wide array of cell subsets with different capacities of engraftment and injured tissue regenerating potential. Proof-of-principle that marrow cells administered locally may engraft and give rise to specialized epithelial cells has been given, but the efficiency of this conversion is too limited to give a therapeutic effect. Besides the identification of plasticity mechanisms, the characterization/isolation of the stem cell subpopulations represents a major challenge to improving the efficacy of transplantation protocols used in regenerative medicine for lung diseases.
Collapse
|
|
19
|
Toonkel RL, Hare JM, Matthay MA, Glassberg MK. Mesenchymal Stem Cells and Idiopathic Pulmonary Fibrosis. Potential for Clinical Testing. Am J Respir Crit Care Med 2013; 188:133-40. [DOI: 10.1164/rccm.201207-1204pp] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
|
|
20
|
Rafat N, Tönshoff B, Bierhaus A, Beck GC. Endothelial progenitor cells in regeneration after acute lung injury: do they play a role? Am J Respir Cell Mol Biol 2013; 48:399-405. [PMID: 23103996 DOI: 10.1165/rcmb.2011-0132tr] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common disorders in patients requiring critical care. The clinical management of these disorders is difficult and unrewarding, and thus they are among the most common causes of death in intensive care units. The activation and damage of pulmonary endothelium comprise the hallmark of ALI/ARDS. Therefore, the recruitment of circulating endothelial progenitor cells (EPCs) to these lesions may exert a beneficial effect on the clinical course of ALI/ARDS. Consequently, cell-based therapies using stem cells to regenerate lung tissue have emerged as potential novel treatment strategies. Although initial studies suggested implantations of exogenously administered bone marrow-derived progenitor cells into damaged vessel walls, recent evidence indicates that this is rather a rare occurrence with uncertain physiologic significance. In the past few years, different populations of progenitor cells were identified, with different functional capacities. This review (1) highlights the different populations of EPCs identified or administered in different models of ALI/ARDS, (2) reports on whether beneficial effects of EPCs could be demonstrated, and (3) puts the conflicting results of different studies into perspective.
Collapse
Affiliation(s)
- Neysan Rafat
- Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
| | | | | | | |
Collapse
|
|
21
|
Knoll A, Brockmeyer T, Chevalier R, Zscheppang K, Nielsen H, Dammann C. Adult Rat Bone Marrow-Derived Stem Cells Promote Late Fetal Type II Cell Differentiation in a Co-Culture Model. Open Respir Med J 2013; 7:46-53. [PMID: 23730368 PMCID: PMC3664445 DOI: 10.2174/1874306401307010046] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 03/08/2013] [Accepted: 03/13/2013] [Indexed: 01/08/2023] Open
Abstract
Bronchopulmonary dysplasia develops in preterm infants due to a combination of lung immaturity and lung injury. Cultured pluripotent bone marrow stem cells (BMSC) are known to reduce injury and induce repair in adult and in immature lungs, possibly through paracrine secretion of soluble factors. The paracrine relationship between BMSC and primary fetal lung epithelial type II cells is unknown. We determined the effects of BMSC on type II cell and fibroblast behavior using an in vitro co-culture model. Rat BMSC were isolated and co-cultured with primary fetal E21 rat type II cells or lung fibroblasts in a Transwell® system without direct cell contact. Effects of BMSC conditioned media (CM) on type II cell and fibroblast proliferation and on type II cell surfactant phospholipid (DSPC) synthesis and mRNA expression of surfactant proteins B and C (sftpb and sftpc) were studied. We also determined the effect of fibroblast and type II cell CM on BMSC proliferation and surface marker expression. Co-culture with BMSC significantly decreased type II cell and fibroblast proliferation to 72.5% and 83.7% of controls, respectively. Type II cell DSPC synthesis was significantly increased by 21% and sftpb and sftpc mRNA expressions were significantly induced (2.1 fold and 2.4 fold, respectively). BMSC proliferation was significantly reduced during the co-culture. Flow cytometry confirmed that BMSC retained the expression of undifferentiated stem cell markers despite their exposure to fetal lung cell CM. We conclude that BMSC induce fetal type II cell differentiation through paracrine release of soluble factors. These studies provide clues for how BMSC may act in promoting alveolar repair following injury.
Collapse
Affiliation(s)
- Ab Knoll
- Hannover Medical School, Hannover, Germany ; Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA, USA
| | | | | | | | | | | |
Collapse
|
|
22
|
Conese M, Carbone A, Castellani S, Di Gioia S. Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases. Cells Tissues Organs 2013; 197:445-73. [PMID: 23652321 DOI: 10.1159/000348831] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2013] [Indexed: 11/19/2022] Open
Abstract
Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders.
Collapse
Affiliation(s)
- Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | | | | | | |
Collapse
|
|
23
|
dos Santos CC, Murthy S, Hu P, Shan Y, Haitsma JJ, Mei SHJ, Stewart DJ, Liles WC. Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 181:1681-92. [PMID: 23083833 DOI: 10.1016/j.ajpath.2012.08.009] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 07/03/2012] [Accepted: 08/02/2012] [Indexed: 12/21/2022]
Abstract
Although bone marrow-derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. Total RNA from lungs, hearts, kidneys, livers, and spleens harvested 28 hours after cecal ligation and puncture was hybridized to mouse expression bead arrays. Common transcriptional responses were analyzed using a network knowledge-based approach. A total of 4751 genes were significantly changed between placebo- and MSC-treated mice (adjusted P ≤ 0.05). Transcriptional responses identified three common effects of MSC administration in all five organs examined: i) attenuation of sepsis-induced mitochondrial-related functional derangement, ii down-regulation of endotoxin/Toll-like receptor innate immune proinflammatory transcriptional responses, and iii) coordinated expression of transcriptional programs implicated in the preservation of endothelial/vascular integrity. Transcriptomic analysis indicates that the protective effect of MSC therapy in sepsis is not limited to a single mediator or pathway but involves a range of complementary activities affecting biological networks playing critical roles in the control of host cell metabolism and inflammatory response.
Collapse
Affiliation(s)
- Claudia C dos Santos
- Interdepartmental Division of Critical Care, The Keenan Research Centre of the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Ontario, Canada.
| | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Angelini DJ, Dorsey RM, Willis KL, Hong C, Moyer RA, Oyler J, Jensen NS, Salem H. Chemical warfare agent and biological toxin-induced pulmonary toxicity: could stem cells provide potential therapies? Inhal Toxicol 2013; 25:37-62. [DOI: 10.3109/08958378.2012.750406] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
25
|
Green MD, Huang SXL, Snoeck HW. Stem cells of the respiratory system: from identification to differentiation into functional epithelium. Bioessays 2012; 35:261-70. [PMID: 23175215 DOI: 10.1002/bies.201200090] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made in the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell-based regenerative medicine for diseases of lung and airways.
Collapse
Affiliation(s)
- Michael D Green
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA
| | | | | |
Collapse
|
|
26
|
Gene-modified mesenchymal stem cells protect against radiation-induced lung injury. Mol Ther 2012; 21:456-65. [PMID: 23299797 DOI: 10.1038/mt.2012.183] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Radiation-induced lung injury (RILI) presents a common and major obstacle in the radiotherapy of thoracic cancers. The aim of this study was to examine whether RILI could be alleviated by mesenchymal stem cells (MSCs) expressing soluble transforming growth factor-β (TGF-β) type II receptor via an adenovirus (Ad-sTβR). Here, we systemically administered male MSCs into female mice challenged with thoracic irradiation. The data showed that either MSCs or Ad-sTβR transduced MSCs (Ad-sTβR-MSCs) specifically migrated into radiation-injured lung. Ad-sTβR-MSCs obviously alleviated lung injury, as reflected by survival and histopathology data, as well as the assays of malondialdehyde (MDA), hydroxyproline, plasma cytokines, and the expression of connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). Furthermore, MSCs and Ad-sTβR-MSCs could adopt the characteristics of alveolar type II (ATII) cells. However, the MSCs levels in the lungs were relatively low to account for the noted therapeutic effects, suggesting the presence of other mechanisms. In vivo, MSCs-conditioned medium (MSCs CM) significantly attenuated RILI. In vitro, MSCs CM protected ATII cells against radiation-induced apoptosis and DNA damage, and modulated the inflammatory response, indicating the beneficial effects of MSCs are largely due to its paracrine activity. Our results provide a novel insight for RILI therapy that currently lack efficient treatments.
Collapse
|
|
27
|
Qin ZH, Xu JF, Qu JM, Zhang J, Sai Y, Chen CM, Wu L, Yu L. Intrapleural delivery of MSCs attenuates acute lung injury by paracrine/endocrine mechanism. J Cell Mol Med 2012; 16:2745-53. [PMID: 22697354 PMCID: PMC4118243 DOI: 10.1111/j.1582-4934.2012.01597.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2012] [Accepted: 06/11/2012] [Indexed: 12/31/2022] Open
Abstract
Two different repair mechanisms of mesenchymal stem cells (MSCs) are suggested to participate in the repair of acute lung injury (ALI): (i) Cell engraftment mechanism, (ii) Paracrine/endocrine mechanism. However, the exact roles they play in the repair remain unclear. The aim of the study was to evaluate the role of paracrine/endocrine mechanism using a novel intrapleural delivery method of MSCs. Either 1 × 10(6) MSCs in 300 μl of PBS or 300 μl PBS alone were intrapleurally injected into rats with endotoxin-induced ALI. On days 1, 3 or 7 after injections, samples of lung tissues and bronchoalveolar lavage fluid (BALF) were collected from each rat for assessment of lung injury, biochemical analysis and histology. The distribution of MSCs was also traced by labelling the cells with 4',6-diamidino-2-phenylindole dihydrochloride (DAPI). MSCs intrapleural injection significantly improved LPS-induced lung histopathology compared with PBS-treated group at day 3. There was also a significant decrease in total cell counts and protein concentration in BALF at day 7 in the MSCs -treated rats compared to PBS control group. Tracking the DAPI-marked MSCs showed that there were no exotic MSCs in the lung parenchyma. MSCs administration resulted in a down-regulation of pro-inflammatory response to endotoxin by reducing TNF-α both in the BALF and in the lung, while up-regulating the anti-inflammatory cytokine IL-10 in the lung. In conclusion, treatment with intrapleural MSCs administration markedly attenuates the severity of endotoxin-induced ALI. This role is mediated by paracrine/endocrine repair mechanism of MSCs rather than by the cell engraftment mechanism.
Collapse
Affiliation(s)
- Zhao-hui Qin
- Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical College, Fudan UniversityShanghai, China
| | - Jin-fu Xu
- Department of Pulmonary Medicine, Shanghai Pulmonary Hospital, Tongji UniversityShanghai, China
| | - Jie-ming Qu
- Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical College, Fudan UniversityShanghai, China
| | - Jing Zhang
- Department of Pulmonary Medicine, Zhongshan Hospital, Shanghai Medical College, Fudan UniversityShanghai, China
| | - Yin Sai
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan UniversityShanghai, China
| | - Chun-mei Chen
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan UniversityShanghai, China
| | - Lian Wu
- Department of Pharmacology & Clinical Pharmacology, University of AucklandNew Zealand
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan UniversityShanghai, China
| |
Collapse
|
|
28
|
Majka SM, Miller HL, Sullivan T, Erickson PF, Kong R, Weiser-Evans M, Nemenoff R, Moldovan R, Morandi SA, Davis JA, Klemm DJ. Adipose lineage specification of bone marrow-derived myeloid cells. Adipocyte 2012; 1:215-229. [PMID: 23700536 PMCID: PMC3609111 DOI: 10.4161/adip.21496] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
We have reported the production of white adipocytes in adipose tissue from hematopoietic progenitors arising from bone marrow. However, technical challenges have hindered detection of this adipocyte population by certain other laboratories. These disparate results highlight the need for sensitive and definitive techniques to identify bone marrow progenitor (BMP)-derived adipocytes. In these studies we exploited new models and methods to enhance detection of this adipocyte population. Here we showed that confocal microscopy with spectrum acquisition could effectively identify green fluorescent protein (GFP) positive BMP-derived adipocytes by matching their fluorescence spectrum to that of native GFP. Likewise, imaging flow cytometry made it possible to visualize intact unilocular and multilocular GFP-positive BMP-derived adipocytes and distinguished them from non-fluorescent adipocytes and cell debris in the cytometer flow stream. We also devised a strategy to detect marker genes in flow-enriched adipocytes from which stromal cells were excluded. This technique also proved to be an efficient means for detecting genetically labeled adipocytes and should be applicable to models in which marker gene expression is low or absent. Finally, in vivo imaging of mice transplanted with BM from adipocyte-targeted luciferase donors showed a time-dependent increase in luciferase activity, with the bulk of luciferase activity confined to adipocytes rather than stromal cells. These results confirmed and extended our previous reports and provided proof-of-principle for sensitive techniques and models for detection and study of these unique cells.
Collapse
|
|
29
|
Zhang H, Fang J, Su H, Yang M, Lai W, Mai Y, Wu Y. Bone marrow mesenchymal stem cells attenuate lung inflammation of hyperoxic newborn rats. Pediatr Transplant 2012; 16:589-98. [PMID: 22738184 DOI: 10.1111/j.1399-3046.2012.01709.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BPD is a significant global health problem and currently lacks effective therapy. We established a neonatal rat model of BPD to investigate therapeutic potential of BMSCs in neonatal lung disease. BMSCs were isolated, identified, and transfected by lentiviral vector carrying GFP gene in vitro. Neonatal rats were injected intravenously with either BMSCs or PBS after they had been already exposed to high oxygen for seven days, and assessed on post-injection day 3, day 7, and day 14 for weight gaining, lung histology, radical alveolar counts, and lung cytokine level. BMSCs were positive for CD29, CD44, and CD90 whereas negative for CD34, CD45, CD11b and with differentiation potential into osteoblasts, adipocytes, and chondrocytes. BMSCs expressed GFP after transfected by lentivirus. After injection, BMSCs exert their therapeutic benefit of improving weight gaining, preventing alveolar growth arrest, and suppressing lung inflammation of neonatal rats. Intravenous delivery of BMSCs in newborn rats conferred protection from hyperoxia-induced lung injury, and one of the effects of BMSCs treatment is suppressing lung inflammation.
Collapse
Affiliation(s)
- Hongshan Zhang
- Department of Pediatric, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.
| | | | | | | | | | | | | |
Collapse
|
|
30
|
Role of bone marrow-derived mesenchymal stem cells in the prevention of hyperoxia-induced lung injury in newborn mice. Cell Biol Int 2012; 36:589-94. [PMID: 22339670 DOI: 10.1042/cbi20110447] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BPD (bronchopulmonary dysplasia) is predominantly characterized by persistent abnormalities in lung structure and arrested lung development, but therapy can be palliative. While promising, the use of BMSC (bone marrow-derived mesenchymal stem cell) in the treatment of lung diseases remains controversial. We have assessed the therapeutic effects of BMSC in vitro and in vivo. In vitro co-culturing with injured lung tissue increased the migration-potential of BMSC; and SP-C (surfactant protein-C), a specific marker of AEC2 (type II alveolar epithelial cells), was expressed. Following intraperitoneal injection of BMSC into experimental BPD mice on post-natal day 7, it was found that BMSC can home to the injured lung, express SP-C, improve pulmonary architecture, attenuate pulmonary fibrosis and increase the survival rate of BPD mice. This work supports the notion that BMSC are of therapeutic benefit through the production of soluble factors at bioactive levels that regulate the pathogenesis of inflammation and fibrosis following hyperoxia.
Collapse
|
|
31
|
Anversa P, Perrella MA, Kourembanas S, Choi AMK, Loscalzo J. Regenerative pulmonary medicine: potential and promise, pitfalls and challenges. Eur J Clin Invest 2012; 42:900-13. [PMID: 22435680 PMCID: PMC3513384 DOI: 10.1111/j.1365-2362.2012.02667.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Chronic lung diseases contribute significantly to the morbidity and mortality of the population. There are few effective treatments for many chronic lung diseases, and even fewer therapies that can arrest or reverse the progress of the disease. DESIGN In this review, we present the current state of regenerative therapies for the treatment of chronic lung diseases. We focus on endothelial progenitor cells, mesenchymal stem cells, and endogenous lung stem/progenitor cells; summarize the work to date in models of lung diseases for each of these therapies; and consider their potential benefits and risks as viable therapies for patients with lung diseases. CONCLUSIONS Cell-based regenerative therapies for lung diseases offer great promise, with preclinical studies suggesting that the next decade should provide the evidence necessary for their ultimate application to our therapeutic armamentarium.
Collapse
Affiliation(s)
- Piero Anversa
- Brigham and Women's Hospital Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | | | | | | | | |
Collapse
|
|
32
|
Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, Rowlands DJ, Quadri SK, Bhattacharya S, Bhattacharya J. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18:759-65. [PMID: 22504485 DOI: 10.1038/nm.2736] [Citation(s) in RCA: 1106] [Impact Index Per Article: 85.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Accepted: 03/16/2012] [Indexed: 12/11/2022]
Abstract
Bone marrow-derived stromal cells (BMSCs) protect against acute lung injury (ALI). To determine the role of BMSC mitochondria in this protection, we airway-instilled mice first with lipopolysaccharide (LPS) and then with either mouse BMSCs (mBMSCs) or human BMSCs (hBMSCs). Live optical studies revealed that the mBMSCs formed connexin 43 (Cx43)-containing gap junctional channels (GJCs) with the alveolar epithelia in these mice, releasing mitochondria-containing microvesicles that the epithelia engulfed. The presence of BMSC-derived mitochondria in the epithelia was evident optically, as well as by the presence of human mitochondrial DNA in mouse lungs instilled with hBMSCs. The mitochondrial transfer resulted in increased alveolar ATP concentrations. LPS-induced ALI, as indicated by alveolar leukocytosis and protein leak, inhibition of surfactant secretion and high mortality, was markedly abrogated by the instillation of wild-type mBMSCs but not of mutant, GJC-incompetent mBMSCs or mBMSCs with dysfunctional mitochondria. This is the first evidence, to our knowledge, that BMSCs protect against ALI by restituting alveolar bioenergetics through Cx43-dependent alveolar attachment and mitochondrial transfer.
Collapse
Affiliation(s)
- Mohammad Naimul Islam
- Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Lau AN, Goodwin M, Kim CF, Weiss DJ. Stem cells and regenerative medicine in lung biology and diseases. Mol Ther 2012; 20:1116-30. [PMID: 22395528 DOI: 10.1038/mt.2012.37] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A number of novel approaches for repair and regeneration of injured lung have developed over the past several years. These include a better understanding of endogenous stem and progenitor cells in the lung that can function in reparative capacity as well as extensive exploration of the potential efficacy of administering exogenous stem or progenitor cells to function in lung repair. Recent advances in ex vivo lung engineering have also been increasingly applied to the lung. The current status of these approaches as well as initial clinical trials of cell therapies for lung diseases are reviewed below.
Collapse
Affiliation(s)
- Allison N Lau
- Department of Genetics, Stem Cell Program, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | | |
Collapse
|
|
34
|
Ohle SJ, Anandaiah A, Fabian AJ, Fine A, Kotton DN. Maintenance and repair of the lung endothelium does not involve contributions from marrow-derived endothelial precursor cells. Am J Respir Cell Mol Biol 2012; 47:11-9. [PMID: 22323363 DOI: 10.1165/rcmb.2011-0180oc] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Lung endothelium is believed to be a quiescent tissue with the potential to exhibit rapid and effective repair after injury. Endothelial progenitor cells derived from the bone marrow have been proposed as one source of new endothelial cells that may directly contribute to pulmonary endothelial cell homeostasis and repair. Here we use bone marrow transplantation models, using purified hematopoietic stem cells (HSCs) or unfractionated whole marrow, to assess engraftment of cells in the endothelium of a variety of tissues. We find scant evidence for any contribution of bone marrow-derived cells to the pulmonary endothelium in the steady state or after recovery from hyperoxia-induced endothelial injury. Although a rare population of CD45-/CD31+/VECadherin+ bone marrow-derived cells, originating from HSCs, can be found in lung tissue after transplantation, these cells are not readily found in anatomic locations that define the pulmonary endothelium. Moreover, by tracking transplanted bone marrow cells obtained from donor transgenic mice containing endothelial lineage-selective reporters (Tie2-GFP), no contribution of bone marrow-derived cells to the adult lung, liver, pancreas, heart, and kidney endothelium can be detected, even after prolonged follow-up periods of 11 months or after recovery from hyperoxic pulmonary endothelial injury. Our findings argue against any significant engraftment of bone marrow-derived cells in the pulmonary vascular endothelium.
Collapse
Affiliation(s)
- Sarah J Ohle
- The Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA
| | | | | | | | | |
Collapse
|
|
35
|
Bernard ME, Kim H, Rajagopalan MS, Stone B, Salimi U, Rwigema JC, Epperly MW, Shen H, Goff JP, Franicola D, Dixon T, Cao S, Zhang X, Wang H, Stolz DB, Greenberger JS. Repopulation of the irradiation damaged lung with bone marrow-derived cells. In Vivo 2012; 26:9-18. [PMID: 22210711 PMCID: PMC3312241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
AIM The effect of lung irradiation on reduction of lung stem cells and repopulation with bone marrow-derived cells was measured. MATERIALS AND METHODS Expression of green fluorescent protein positive cells (GFP(+)) in the lungs of thoracic irradiated FVB/NHsd mice (Harlan Sprague Dawley, Indianapolis, IN, USA) was determined. This was compared to the repopulation of bone marrow-derived cells found in the lungs from naphthalene treated male FVB/NHsd mice and gangciclovir (GCV) treated FeVBN GFP(+) male marrow chimeric HSV-TK-CCSP. The level of mRNA for lung stem cell markers clara cell (CCSP), epithelium 1 (FOXJ1) and surfactant protein C (SP-C), and sorted single cells positive for marrow origin epithelial cells (GFP(+)CD45(-)) was measured. RESULTS The expression of pulmonary stem cells as determined by PCR was reduced most by GCV, then naphthalene, and least by thoracic irradiation. Irradiation, like GCV, reduced mRNA expression of CCSP, CYP2F2, and FOXJ1, while naphthalene reduced that of CCSP and CYP2F2. Ultrastructural analysis showed GFP(+) pulmonary cells of bone marrow origin, with the highest frequency being found in GCV-treated groups. CONCLUSION Bone marrow progenitor cells may not participate in the repopulation of the lung following irradiation.
Collapse
Affiliation(s)
- Mark E. Bernard
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Hyun Kim
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Malolan S. Rajagopalan
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Brandon Stone
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Umar Salimi
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Jean-Claude Rwigema
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Michael W. Epperly
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Hongmei Shen
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Julie P. Goff
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Darcy Franicola
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Tracy Dixon
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Shaonan Cao
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Xichen Zhang
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Hong Wang
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Donna B. Stolz
- Department of Cell Biology and Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Joel S. Greenberger
- Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| |
Collapse
|
|
36
|
Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S, Rojas M, Stripp B, Warburton D, Prockop DJ. Stem cells and cell therapies in lung biology and lung diseases. PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY 2011; 8:223-72. [PMID: 21653527 PMCID: PMC3132784 DOI: 10.1513/pats.201012-071dw] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 02/03/2011] [Indexed: 11/20/2022]
Abstract
The University of Vermont College of Medicine and the Vermont Lung Center, with support of the National Heart, Lung, and Blood Institute (NHLBI), the Alpha-1 Foundation, the American Thoracic Society, the Emory Center for Respiratory Health,the Lymphangioleiomyomatosis (LAM) Treatment Alliance,and the Pulmonary Fibrosis Foundation, convened a workshop,‘‘Stem Cells and Cell Therapies in Lung Biology and Lung Diseases,’’ held July 26-29, 2009 at the University of Vermont,to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy approaches for lung diseases. These are rapidly expanding areas of study that provide further insight into and challenge traditional views of the mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases.
Collapse
Affiliation(s)
- Daniel J Weiss
- Vermont Lung Center, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
De Paepe ME, Mao Q, Ghanta S, Hovanesian V, Padbury JF. Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:1329-39. [PMID: 21356383 DOI: 10.1016/j.ajpath.2010.11.062] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Revised: 10/25/2010] [Accepted: 11/17/2010] [Indexed: 01/26/2023]
Abstract
The role of umbilical cord blood (CB)-derived stem cell therapy in neonatal lung injury remains undetermined. We investigated the capacity of human CB-derived CD34(+) hematopoietic progenitor cells to regenerate injured alveolar epithelium in newborn mice. Double-transgenic mice with doxycycline (Dox)-dependent lung-specific Fas ligand (FasL) overexpression, treated with Dox between embryonal day 15 and postnatal day 3, served as a model of neonatal lung injury. Single-transgenic non-Dox-responsive littermates were controls. CD34(+) cells (1 × 10(5) to 5 × 10(5)) were administered at postnatal day 5 by intranasal inoculation. Engraftment, respiratory epithelial differentiation, proliferation, and cell fusion were studied at 8 weeks after inoculation. Engrafted cells were readily detected in all recipients and showed a higher incidence of surfactant immunoreactivity and proliferative activity in FasL-overexpressing animals compared with non-FasL-injured littermates. Cord blood-derived cells surrounding surfactant-immunoreactive type II-like cells frequently showed a transitional phenotype between type II and type I cells and/or type I cell-specific podoplanin immunoreactivity. Lack of nuclear colocalization of human and murine genomic material suggested the absence of fusion. In conclusion, human CB-derived CD34(+) cells are capable of long-term pulmonary engraftment, replication, clonal expansion, and reconstitution of injured respiratory epithelium by fusion-independent mechanisms. Cord blood-derived surfactant-positive epithelial cells appear to act as progenitors of the distal respiratory unit, analogous to resident type II cells. Graft proliferation and alveolar epithelial differentiation are promoted by lung injury.
Collapse
Affiliation(s)
- Monique E De Paepe
- Department of Pathology, Women and Infants Hospital, Providence, Rhode Island 02905, USA.
| | | | | | | | | |
Collapse
|
|
38
|
Hind M, Maden M. Is a regenerative approach viable for the treatment of COPD? Br J Pharmacol 2011; 163:106-15. [PMID: 21265829 PMCID: PMC3085872 DOI: 10.1111/j.1476-5381.2011.01246.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 01/03/2011] [Accepted: 01/06/2011] [Indexed: 12/23/2022] Open
Abstract
Degenerative lung diseases such as chronic obstructive pulmonary disease (COPD) are common with huge worldwide morbidity. Anti-inflammatory drug development strategies have proved disappointing and current treatment is aimed at symptomatic relief. Only lung transplantation with all its attendant difficulties offers hope of cure and the outlook for affected patients is bleak. Lung regeneration therapies aim to reverse the structural and functional deficits in COPD either by delivery of exogenous lung cells to replace lost tissue, delivery of exogenous stem cells to induce a local paracrine effect probably through an anti-inflammatory action or by the administration of small molecules to stimulate the endogenous regenerative ability of lung cells. In animal models of emphysema and disrupted alveolar development each of these strategies has shown some success but there are potential tumour-inducing dangers with a cellular approach. Small molecules such as all-trans retinoic acid have been successful in animal models although the mechanism is not completely understood. There are currently two Pharma-sponsored trials in progress concerning patients with COPD, one of a specific retinoic acid receptor gamma agonist and another using mesenchymal stem cells.
Collapse
Affiliation(s)
- Matthew Hind
- Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK.
| | | |
Collapse
|
|
39
|
Selman M, Pardo A, Richeldi L, Cerri S. Emerging drugs for idiopathic pulmonary fibrosis. Expert Opin Emerg Drugs 2011; 16:341-62. [DOI: 10.1517/14728214.2011.565049] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
|
|
40
|
MOODLEY Y, MANUELPILLAI U, WEISS DJ. Cellular therapies for lung disease: A distant horizon. Respirology 2011; 16:223-37. [DOI: 10.1111/j.1440-1843.2010.01914.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
41
|
Sueblinvong V, Weiss DJ. Stem cells and cell therapy approaches in lung biology and diseases. Transl Res 2010; 156:188-205. [PMID: 20801416 PMCID: PMC4201367 DOI: 10.1016/j.trsl.2010.06.007] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2010] [Revised: 06/14/2010] [Accepted: 06/16/2010] [Indexed: 12/19/2022]
Abstract
Cell-based therapies with embryonic or adult stem cells, including induced pluripotent stem cells, have emerged as potential novel approaches for several devastating and otherwise incurable lung diseases, including emphysema, pulmonary fibrosis, pulmonary hypertension, and the acute respiratory distress syndrome. Although initial studies suggested engraftment of exogenously administered stem cells in lung, this is now generally felt to be a rare occurrence of uncertain physiologic significance. However, more recent studies have demonstrated paracrine effects of administered cells, including stimulation of angiogenesis and modulation of local inflammatory and immune responses in mouse lung disease models. Based on these studies and on safety and initial efficacy data from trials of adult stem cells in other diseases, groundbreaking clinical trials of cell-based therapy have been initiated for pulmonary hypertension and for chronic obstructive pulmonary disease. In parallel, the identity and role of endogenous lung progenitor cells in development and in repair from injury and potential contribution as lung cancer stem cells continue to be elucidated. Most recently, novel bioengineering approaches have been applied to develop functional lung tissue ex vivo. Advances in each of these areas will be described in this review with particular reference to animal models.
Collapse
Key Words
- aec, alveolar epithelial cell
- ali, acute lung injury
- ards, acute respiratory distress syndrome
- basc, bronchioalveolar stem cell
- ccsp, clara cell secretory protein
- cf, cystic fibrosis
- cftr, cystic fibrosis transmembrane conductance regulator
- clp, cecal ligation and puncture
- copd, chronic obstructive pulmonary disease
- enos, endothelial nitric oxide synthetase
- epc, endothelial progenitor cell
- esc, embryonic stem cell
- fev1, forced expiratory volume in 1 second
- fvc, forced vital capacity
- gfp, green fluorescent protein
- hsc, hematopoietic stem cell
- ipf, idiopathic pulmonary fibrosis
- kgf, keratinocyte growth factor
- lps, lipopolysaccharide
- mct, monocrotaline
- mhc, major histocompatibility complex
- msc, mesenchymal stromal (stem) cell
- ph, pulmonary hypertension
- pro-spc, pro-surfactant protein c
- sca-1, stem cell antigen-1
Collapse
Affiliation(s)
- Viranuj Sueblinvong
- Division of Pulmonary, Critical Care and Allergy, Department of Medicine, Emory University, Atlanta, GA, USA
| | | |
Collapse
|
|
42
|
D'Agostino B, Sullo N, Siniscalco D, De Angelis A, Rossi F. Mesenchymal stem cell therapy for the treatment of chronic obstructive pulmonary disease. Expert Opin Biol Ther 2010; 10:681-7. [PMID: 20384521 DOI: 10.1517/14712591003610614] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Recent studies have revealed that adult stem cells such as bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells may be a potent next-generation therapy for COPD. Pathogenesis of COPD is characterized by an upregulation of inflammatory processes leading to irreversible events such as apoptosis of epithelial cells, proteolysis of the terminal air-space and lung extracellular matrix components. The available pharmacological treatments are essentially symptomatic, therefore, there is a need to develop more effective therapeutic strategies. It has been previously demonstrated that transplanted MSC home to the lung in response to lung injury and adopt phenotypes of alveolar epithelial cells, endothelial cells, fibroblasts and bronchial epithelial cells. However, engraftment and differentiation are now felt to be rare occurrences and other mechanisms might be involved and play a more important role. Importantly, MSCs protect lung tissue through suppression of proinflammatory cytokines, and through triggering production of reparative growth factors. Accordingly, it is not clear if and how these cells will be able to repair, to slow or to prevent the disease. This article reviews recent advances in regenerative medicine in COPD and highlights that their potential application although promising and very attractive, are still a far away opinion.
Collapse
Affiliation(s)
- Bruno D'Agostino
- Department of Experimental Medicine, Second University of Naples, Section of Pharmacology L Donatelli, via S Maria di Costantinopoli, 16-80138 Napoli, Italy.
| | | | | | | | | |
Collapse
|
|
43
|
Piro D, Rejman J, Conese M. Stem cell therapy for cystic fibrosis: current status and future prospects. Expert Rev Respir Med 2010; 2:365-80. [PMID: 20477199 DOI: 10.1586/17476348.2.3.365] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Although cystic fibrosis (CF), an autosomal recessive disease caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), seems a good candidate for gene therapy, 15 years of intense investigation and a number of clinical trials have not yet produced a viable clinical gene-therapy strategy. In addition, the duration of gene expression has been shown to be limited, only lasting 1-4 weeks. Therefore, alternative approaches involve the search for, and use of, stem cell populations. Bone marrow contains different stem cell types, including hematopoietic stem cells and multipotent mesenchymal stromal cells. Numerous studies have now demonstrated the ability of hematopoietic stem cells and mesenchymal stromal cells to home to the lung and differentiate into epithelial cells of both the conducting airways and the alveolar region. However, engraftment of bone marrow-derived stem cells into the airways is a very inefficient process. Detailed knowledge of the cellular and molecular determinants governing homing to the lung and transformation of marrow cells into lung epithelial cells would benefit this process. Despite a very low level of engraftment of donor cells into the nose and gut, significant CFTR mRNA expression and a measurable level of correction of the electrophysiological defect were observed after transplantation of wild-type marrow cells into CF mice. It is uncertain whether this effect is due to the presence of CFTR-expressing epithelial cells derived from donor cells or to the immunomodulatory role of transplanted cells. Finally, initial studies on the usefulness of umbilical cord blood and embryonic stem cells in the generation of airway epithelial cells will be discussed in this review.
Collapse
Affiliation(s)
- Donatella Piro
- Department of Biomedical Sciences, University of Foggia, c/o Ospedali Riuniti, Viale L. Pinto 1, 71100 Foggia, Italy.
| | | | | |
Collapse
|
|
44
|
Kassmer SH, Krause DS. Detection of bone marrow-derived lung epithelial cells. Exp Hematol 2010; 38:564-73. [PMID: 20447442 PMCID: PMC2909593 DOI: 10.1016/j.exphem.2010.04.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2010] [Revised: 04/21/2010] [Accepted: 04/23/2010] [Indexed: 10/19/2022]
Abstract
Studies on the ability of bone marrow-derived cells to adopt the morphology and protein expression pattern of epithelial cells in vivo have expanded rapidly during the last decade, and hundreds of publications report that bone marrow-derived cells can become epithelial cells of multiple organs, including lung, liver, gastrointestinal tract, skin, pancreas, and others. In this review, we critically evaluate the literature related to engraftment of bone marrow-derived cells as epithelial cells in the lung. More than 40 articles focused on whether bone marrow cells can differentiate into lung epithelial cells have been published, nearly all of which claim to identify marrow-derived epithelial cells. A few investigations have concluded that no such cells are present and that the phenomenon of marrow-derived epithelial cells is based on detection artifacts. Here we discuss the problems that exist in published articles identifying marrow-derived epithelial cells, and propose standards for detection methods that provide the most definitive data. Identification of bone marrow-derived epithelial cells requires reliable and sensitive techniques for their detection, which must include cell identification based on the presence of an epithelial marker and the absence of blood cell markers as well as a marker for donor bone marrow origin. In order for these studies to be rigorous, they must also use approaches to rule out cell overlap by microscopy or single-cell isolation. Once these stringent criteria for identification of marrow-derived epithelial cells are used universally, then the field can move forward to address the critical questions about which bone marrow-derived cells are responsible for engraftment as epithelial cells, the mechanisms by which this occurs, whether these cells play a role in normal tissue repair, and whether specific cell subsets can be used for therapeutic benefit.
Collapse
Affiliation(s)
- Susannah H Kassmer
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06509, USA.
| | | |
Collapse
|
|
45
|
Wang D, Morales JE, Calame DG, Alcorn JL, Wetsel RA. Transplantation of human embryonic stem cell-derived alveolar epithelial type II cells abrogates acute lung injury in mice. Mol Ther 2010; 18:625-34. [PMID: 20087316 DOI: 10.1038/mt.2009.317] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Respiratory diseases are a major cause of mortality and morbidity worldwide. Current treatments offer no prospect of cure or disease reversal. Transplantation of pulmonary progenitor cells derived from human embryonic stem cells (hESCs) may provide a novel approach to regenerate endogenous lung cells destroyed by injury and disease. Here, we examine the therapeutic potential of alveolar type II epithelial cells derived from hESCs (hES-ATIICs) in a mouse model of acute lung injury. When transplanted into lungs of mice subjected to bleomycin (BLM)-induced acute lung injury, hES-ATIICs behaved as normal primary ATIICs, differentiating into cells expressing phenotypic markers of alveolar type I epithelial cells. Without experiencing tumorigenic side effects, lung injury was abrogated in mice transplanted with hES-ATIICs, demonstrated by recovery of body weight and arterial blood oxygen saturation, decreased collagen deposition, and increased survival. Therefore, transplantation of hES-ATIICs shows promise as an effective therapeutic to treat acute lung injury.
Collapse
Affiliation(s)
- Dachun Wang
- Research Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA
| | | | | | | | | |
Collapse
|
|
46
|
Balasubramaniam V, Ryan SL, Seedorf GJ, Roth EV, Heumann TR, Yoder MC, Ingram DA, Hogan CJ, Markham NE, Abman SH. Bone marrow-derived angiogenic cells restore lung alveolar and vascular structure after neonatal hyperoxia in infant mice. Am J Physiol Lung Cell Mol Physiol 2009; 298:L315-23. [PMID: 20008116 DOI: 10.1152/ajplung.00089.2009] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Neonatal hyperoxia impairs vascular and alveolar growth in mice and decreases endothelial progenitor cells. To determine the role of bone marrow-derived cells in restoration of neonatal lung structure after injury, we studied a novel bone marrow myeloid progenitor cell population from Tie2-green fluorescent protein (GFP) transgenic mice (bone marrow-derived angiogenic cells; BMDAC). We hypothesized that treatment with BMDAC would restore normal lung structure in infant mice during recovery from neonatal hyperoxia. Neonatal mice (1-day-old) were exposed to 80% oxygen for 10 days. BMDACs (1 x 10(5)), embryonic endothelial progenitor cells, mouse embryonic fibroblasts (control), or saline were then injected into the pulmonary circulation. At 21 days of age, saline-treated mice had enlarged alveoli, reduced septation, and a reduction in vascular density. In contrast, mice treated with BMDAC had complete restoration of lung structure that was indistinguishable from room air controls. BMDAC comprised 12% of distal lung cells localized to pulmonary vessels or alveolar type II (AT2) cells and persist (8.8%) for 8 wk postinjection. Coculture of AT2 cells or lung endothelial cells (luEC) with BMDAC augmented AT2 and luEC cell growth in vitro. We conclude that treatment with BMDAC after neonatal hyperoxia restores lung structure in this model of bronchopulmonary dysplasia.
Collapse
Affiliation(s)
- Vivek Balasubramaniam
- Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado-Denver, 12800 E. 19th Ave., Aurora, CO 80045, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Cargnoni A, Gibelli L, Tosini A, Signoroni PB, Nassuato C, Arienti D, Lombardi G, Albertini A, Wengler GS, Parolini O. Transplantation of allogeneic and xenogeneic placenta-derived cells reduces bleomycin-induced lung fibrosis. Cell Transplant 2009; 18:405-22. [PMID: 19622228 DOI: 10.3727/096368909788809857] [Citation(s) in RCA: 186] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Fetal membranes (amnion and chorion) have recently raised significant attention as potential sources of stem cells. We have recently demonstrated that cells derived from human term placenta show stem cell phenotype, high plasticity, and display low immunogenicity both in vitro and in vivo. Moreover, placenta-derived cells, after xenotransplantation, are able to engraft in solid organs including the lung. On these bases, we studied the effects of fetal membrane-derived cells on a mouse model of bleomycin-induced lung fibrosis. Fetal membrane-derived cells were infused 15 min after intratracheal bleomycin instillation. Different delivery routes were used: intraperitoneal or intratracheal for both xenogeneic and allogeneic cells, and intravenous for allogeneic cells. The effects of the transplanted cells on bleomycin-induced inflammatory and fibrotic processes were then scored and compared between transplanted and control animals at different time points. By PCR and immunohistochemistry analyses, we demonstrated the presence of transplanted cells 3, 7, 9, and 14 days after transplantation. Concomitantly, we observed a clear decrease in neutrophil infiltration and a significant reduction in the severity of bleomycin-induced lung fibrosis in mice treated with placenta-derived cells, irrespective of the source (allogeneic or xenogeneic) or delivery route. Our findings constitute further evidence in support of the hypothesis that placenta-derived cells could be useful for clinical application, and warrant further studies toward the use of these cells for the repair of tissue damage associated with inflammatory and fibrotic degeneration.
Collapse
Affiliation(s)
- Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, 25124 Brescia, Italy
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
May LA, Kicic A, Rigby P, Heel K, Pullen TL, Crook M, Charles A, Banerjee B, Ravine D, Saxena A, Musk M, Stick SM, Chambers DC. Cells of epithelial lineage are present in blood, engraft the bronchial epithelium, and are increased in human lung transplantation. J Heart Lung Transplant 2009; 28:550-7. [PMID: 19481014 DOI: 10.1016/j.healun.2009.03.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2008] [Revised: 03/03/2009] [Accepted: 03/05/2009] [Indexed: 10/20/2022] Open
Abstract
BACKGROUND There is a growing expectation that cell-based therapies will prove effective for a wide range of conditions including lung diseases such as cystic fibrosis. The promise of these therapies will depend largely on effective delivery and engraftment. In this study, in the setting of human lung transplantation, we sought to determine whether exogenous epithelial cells are able to engraft the transplanted organ and if cells of a similar phenotype could be detected in peripheral blood. METHODS Cells obtained from bronchial brushings and peripheral blood were analyzed via dual fluorescent in situ hybridization/fluorescent immunohistochemistry (FISH/IHC), short tandem repeat polymerase chain reaction (STR-PCR) and flow cytometry. RESULTS In 2 of 3 gender-mismatched patients we observed limited (5.9% to 6.8% by STR-PCR and 3.5% to 4% by FISH/IHC) engraftment of the bronchial epithelium by exogenous epithelial cells. Engrafting cells were CD34(-) CD15(-) CD68(-) c-Kit(-), but expressed CXCR4 on the cell surface. Cells with a similar phenotype were also identified in peripheral blood. In 8 patients, at 2 to 66 months post-transplant, 0.57 +/- 0.17% of CD14(-) peripheral blood mononuclear cells were of epithelial lineage. Almost all were CD45(+) and most expressed CXCR4 on the cell membrane. Cells of epithelial lineage were also identified in peripheral blood in healthy individuals but in much lower numbers (0.08 +/- 0.01%, p < 0.05). CONCLUSIONS Cells of epithelial lineage are detectable in peripheral blood and are able to engraft the bronchial epithelium in humans. Cell numbers are increased in lung transplantation.
Collapse
Affiliation(s)
- Leigh A May
- Telethon Institute for Child Health Research, Subiaco, Western Australia, Australia
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
van Haaften T, Byrne R, Bonnet S, Rochefort GY, Akabutu J, Bouchentouf M, Rey-Parra GJ, Galipeau J, Haromy A, Eaton F, Chen M, Hashimoto K, Abley D, Korbutt G, Archer SL, Thébaud B. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med 2009; 180:1131-42. [PMID: 19713449 DOI: 10.1164/rccm.200902-0179oc] [Citation(s) in RCA: 352] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
RATIONALE Bronchopulmonary dysplasia (BPD) and emphysema are characterized by arrested alveolar development or loss of alveoli; both are significant global health problems and currently lack effective therapy. Bone marrow-derived mesenchymal stem cells (BMSCs) prevent adult lung injury, but their therapeutic potential in neonatal lung disease is unknown. OBJECTIVES We hypothesized that intratracheal delivery of BMSCs would prevent alveolar destruction in experimental BPD. METHODS In vitro, BMSC differentiation and migration were assessed using co-culture assays and a modified Boyden chamber. In vivo, the therapeutic potential of BMSCs was assessed in a chronic hyperoxia-induced model of BPD in newborn rats. MEASUREMENTS AND MAIN RESULTS In vitro, BMSCs developed immunophenotypic and ultrastructural characteristics of type II alveolar epithelial cells (AEC2) (surfactant protein C expression and lamellar bodies) when co-cultured with lung tissue, but not with culture medium alone or liver. Migration assays revealed preferential attraction of BMSCs toward oxygen-damaged lung versus normal lung. In vivo, chronic hyperoxia in newborn rats led to air space enlargement and loss of lung capillaries, and this was associated with a decrease in circulating and resident lung BMSCs. Intratracheal delivery of BMSCs on Postnatal Day 4 improved survival and exercise tolerance while attenuating alveolar and lung vascular injury and pulmonary hypertension. Engrafted BMSCs coexpressed the AEC2-specific marker surfactant protein C. However, engraftment was disproportionately low for cell replacement to account for the therapeutic benefit, suggesting a paracrine-mediated mechanism. In vitro, BMSC-derived conditioned medium prevented O(2)-induced AEC2 apoptosis, accelerated AEC2 wound healing, and enhanced endothelial cord formation. CONCLUSIONS BMSCs prevent arrested alveolar and vascular growth in part through paracrine activity. Stem cell-based therapies may offer new therapeutic avenues for lung diseases that currently lack efficient treatments.
Collapse
Affiliation(s)
- Timothy van Haaften
- Department of Pediatrics, Women and Children Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Stem cells and cell therapies in lung biology and lung diseases. Ann Am Thorac Soc 2008; 5:637-67. [PMID: 18625757 DOI: 10.1513/pats.200804-037dw] [Citation(s) in RCA: 134] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
|