Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis
Abstract
:1. Introduction
1.1. The Alveolar Compartment and the Development of Pathological Fibrosis
1.2. Modeling Lung Fibrosis
2. Regeneration and Stem/Progenitor Cells
2.1. Epithelial Stem and Progenitor Cells Are Contributing to Regenerate the Alveolar Epithelium
2.2. Mechanisms of Alveolar Regeneration
2.3. Alveolar Regeneration in Human Lungs
3. Cell Therapy in Lung Fibrosis
3.1. Preclinical Mouse Studies
3.1.1. Epithelial Cells: Alveolar Type 2 Cells
3.1.2. Adult Mesenchymal Stromal/Stem Cells
3.1.3. Induced Pluripotent Stem Cells
3.2. Clinical Human Studies
Type of Study | Cell Source | Cell Delivery Route, Dose and Time of Administration | Time of Readouts and Results | Ref |
---|---|---|---|---|
Preclinical mouse studies | AT2 cells | Intratracheal route. A dose of 2.5 × 106 cells/rat 14 days after a single intratracheal bleomycin administration | The animals were euthanized 21 days after bleomycin challenge. Treated rats after bleomycin instillation showed a reduction in the degree of fibrosis and a complete recovery to normal levels of surfactant proteins | [145] |
AT2 cells | Intratracheal route. A dose of 2.5 × 106 cells/rat 3, 7 or 15 days after a single intratracheal bleomycin administration | The animals were euthanized 21 days after bleomycin challenge. Treated rats after bleomycin instillation showed reduced collagen deposition and reduction in the severity of pulmonary fibrosis (regardless the time point of AT2 cell treatment) | [146] | |
AT2 cells | Intratracheal route. A dose of 2.5 × 106 cells/rat 3 or 7 days after a single intratracheal bleomycin administration | The animals were euthanized 7 or 14 days after bleomycin challenge. Treated rats 7 days after bleomycin instillation showed an improvement in lung performance, structure and surfactant ultrastructure in bleomycin-induced lung fibrosis, while those treated 3 days after bleomycin instillation were only able to slightly recover the volume of AT2 and volume fraction of lamellar bodies in AT2 | [147] | |
Adult lung spheroid cells (LSCs) | Intravenous route. A dose of either 5 × 106 syngeneic or allogeneic LSCs/rat 24 h after a single intratracheal bleomycin administration | The animals were euthanized 14 days after bleomycin challenge. Treated rats with allogeneic/syngeneic LSCs show an attenuation in the progression and severity of pulmonary fibrosis, decreasing apoptosis, protecting alveolar structures and increasing angiogenesis. Safety and efficacy of allogeneic LSCs treatment is demonstrated | [148] | |
Human BM-MSCs | Intravenous route. A dose of 5 × 10⁵ cells/humanized mouse 2 days after a single intratracheal bleomycin administration | The animals were euthanized 7 or 21 days after bleomycin challenge. Treated humanized mice with human MSCs showed an attenuation of pulmonary fibrosis development. MSCs are suggested to suppress T-cell overactivation via PD-1 and PD-L1 interaction. Human MSCs have a therapeutic effect only in the early phase of pulmonary fibrosis | [151] | |
Human BM-MSCs | Intravenous route. A dose of 0.5 × 106 modified * or nonmodified cells/mouse 7 days after a single intratracheal bleomycin administration. * Cell modification refers to their prior transduction of miRNAs (let-7d or miR-154) using lentiviral vectors | The animals were euthanized 14 days after bleomycin challenge. Treated mice with human modified (let-7d) MSCs revealed shifts in animal weight loss, collagen activity after treatment and decrease in CD45+ cells, partially reducing the effects of bleomycin-induced lung injury. This study suggests the use of miRNA-modified BM-MSCs as a potential therapeutic strategy | [152] | |
BM-MSCs | Intravenous route. A dose of 5 × 10⁵ cells/mouse immediately after or 7 days after a single intratracheal bleomycin administration | The animals were euthanized 14 days after bleomycin challenge. Immediately after bleomycin instillation, treated mice showed an amelioration in the fibrotic injuries, while those treated 7 days after bleomycin instillation, even though engraftment was not inhibited, the ability of the cells to alter the course of disease progression was eliminated | [155] | |
BM-MSCs | Intravenous route. A dose of 2.5 × 106 cells/rat immediately after or 7 days after a single intratracheal bleomycin administration | The animals were euthanized 7, 14 or 28 days after bleomycin challenge. The present study demonstrates that when MSCs were administered after bleomycin challenge, exogenous MSCs were immediately detected in lung tissues from rats sacrificed at different time points and the number of MSCs in the lung tissue increased over time, while this did not happen to the group treated after 7 days of bleomycin instillation | [156] | |
BM-MSCs | Intravenous route. Two doses of 0.5 × 106 cells/mouse. The first one was administered after a single oropharyngeal bleomycin administration and the second dose, 3 days after the first dose | The animals were euthanized 14 days after bleomycin challenge. This study demonstrates that BM-MSCs expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced lung fibrosis | [157] | |
Human BM-MSCs | Intravenous route. A dose of 5 × 10⁵/mouse 24 h after a single intratracheal bleomycin administration | The animals were euthanized 14 days after bleomycin challenge. In this study, the authors show that MSCs can correct the inadequate communication between epithelial and mesenchymal cells through STC1 (Stanniocalcin-1) secretion after bleomycin instillation | [158] | |
BM-MSCs | Intratracheal route. A dose of either 5 × 10⁵ hypoxia-preconditioned or control cells/mouse 3 days after a single intratracheal bleomycin administration | The animals were euthanized 7 or 21 days after bleomycin challenge. This study reports that hypoxia-preconditioned BM-MSCs improve pulmonary functions and reduce inflammatory and fibrotic mediators after bleomycin-induced lung fibrosis | [159] | |
Oncostatin M (OSM)-preconditioned BM-MSCs | Intratracheal route. A dose of either 2 × 10⁵ oncostatin M (OSM)-preconditioned or control cells/mouse 3 days after a single intratracheal bleomycin administration | The animals were euthanized 7 or 21 days after bleomycin challenge. Transplantation of OSM-preconditioned MSCs significantly improved pulmonary respiratory functions and downregulated expression of inflammatory factors and fibrotic factors after bleomycin instillation | [160] | |
BM-MSCs | Intravenous route. A dose of 1 × 106 cells/mL/rat 14 days after a single intratracheal bleomycin administration | The animals were euthanized 28 days after bleomycin challenge. Animals treated with BM-MSCs showed a significant decrease in the alveolar wall thickening, in the inflammatory infiltrate and in the collagen fiber deposition. The conclusion of the study was that the therapeutic pulmonary anti-fibrotic activity of BM-MSCs is mediated through their anti-inflammatory properties and inhibition of SMAD-3/TGFβ expression | [161] | |
Resident lung MSCs (luMSCs) | Intravenous route. A dose of either 0.15 × 106 or 0.25 × 106 cells/mouse immediately after a single intratracheal bleomycin administration | The animals were euthanized 14 or 35 days after bleomycin challenge. Treated animals showed a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and display reduced collagen deposition. Also, treatment with luMSCs significantly decreased weight loss associated with bleomycin and increased survival from 50% at 14 days with bleomycin alone to 80% when mice had been treated with luMSCs | [162] | |
BM-MSCs | Intravenous route. A dose of 5 × 10⁴ allogeneic cells/g/mouse 6–8 h or 9 days after a single intranasal bleomycin administration | The animals were euthanized 28 days after bleomycin challenge. Early treatment with allogeneic MSCs protected the lung architecture and significantly reduced fibrosis, apoptosis and IL1-production, while delayed MSC treatment failed to protect the mice from bleomycin-induced lung fibrosis. Of note, this is the first study to definitively show the importance of naturally derived HFG in MSC protection in the bleomycin model | [164] | |
Amnion-MSCs vs. BM-MSCs vs. human amniotic epithelial cells (hAECs) | Intravenous route. A dose of 1 × 106 cells/mouse 3 days after introducing the second bleomycin injury (bleomycin administration was done intra-nasally, and the second dose was given 7 days after the first one) | The animals were euthanized 17 or 31 days after bleomycin challenge. This study concluded that amnion-MSCs may be more effective than BM-MSCs and hAECs in reducing injury following delayed injection in the setting of repeated lung injury | [165] | |
ADSCs | Intravenous route. A dose of either 5 × 10⁵ young-donor or old-donor cells/mouse 24 h after a single intratracheal bleomycin administration | The animals were euthanized 21 days after bleomycin challenge. Treated old mice with young ADSC displayed a greater reduction in fibrosis, oxidative stress, MMP-2 activity and apoptosis markers than mice treated with old ADSCs | [168] | |
ADSCs | Intravenous route. A dose of either 2.5 × 10⁴ or 2.5 × 10⁵ cells/mouse immediately after subcutaneous bleomycin administration for 7 days | The animals were euthanized 7 or 21 days after bleomycin challenge. ADCSs accumulated in the pulmonary interstitium and inhibited both inflammation and fibrosis in the lung. Treated mice showed decreased lung fibrosis and inflammation in a dose-dependent manner | [169] | |
ADSCs (human) | Intraperitoneal route. During the latter 2 months of bleomycin exposure * 3 × 10⁵ human cells were administered repeatedly at the same time as bleomycin. * Bleomycin was injected intratracheally in eight biweekly doses | The animals were euthanized 14 days after bleomycin challenge. Treated mice showed decreased lung fibrosis, inflammatory cell infiltration, epithelial hyperplasia, TGFβ expression and epithelial apoptosis | [170] | |
ADSCs | Intravenous route. A dose of 5 × 10⁵ cells/mouse 24 h after a single intratracheal bleomycin administration | Mice treated with ADSCs showed attenuated bleomycin-induced lung and skin fibrosis and accelerated wound healing. This study suggests that ADSCs may prime injured tissues and prevent end-organ fibrosis | [171] | |
ADSCs (human) | Intravenous route. A dose of 40 × 106/kg body weight/mouse 3, 6 and 9 days after a single intratracheal bleomycin administration | The animals were euthanized 24 days after bleomycin challenge. Mice treated with ADSCs showed a higher increase in survivability, organ weight reduction and collagen deposition when compared to those treated with pirfenidone. Also, ADSCs potently suppressed profibrotic genes induced by bleomycin and also inhibited pro-inflammatory related transcripts | [172] | |
Human Placental MSCs of fetal origins (hfPMSCs) | Intravenous route. A dose of 1 × 10⁵ cells/mouse 3 days after a single intratracheal bleomycin administration | The animals were euthanized 0, 7 and 28 days after bleomycin challenge. Treatment with hfPMSCs showed that these cells can attenuate bleomycin-induced lung inflammation and fibrosis in mice, in part through a mechanism by attenuating MyD88-mediated inflammation | [173] | |
Amniotic fluid stem cells (AFSCs) | Intravenous route. A dose of 1 × 106 cells/mouse either 2 h or 14 days after a single intratracheal bleomycin administration | The animals were euthanized 3, 14, 28 days after bleomycin challenge, depending on the group. Treated mice at both time points showed inhibition in the changes in lung function associated with bleomycin-induced lung injury and decreased collagen deposition | [174] | |
iPSCs | Intravenous route. A dose of 2 × 106 cells/mouse 24 h after a single intratracheal bleomycin administration | The animals were euthanized 21 days after bleomycin challenge. Treated mice after bleomycin showed an inhibition of EMT, inflammatory response and TGF-β1/Smad2/3 signaling pathway | [175] | |
iPSCs | Intravenous route. A dose of 2 × 106 cells/mouse (cells either lacking c-Myc or in condition medium) 24 h after a single intratracheal bleomycin administration | The animals were euthanized 3, 7, 14 or 21 days after bleomycin challenge. Treated mice, after bleomycin instillation, showed an attenuation in collagen content, diminished neutrophil accumulation and rescued pulmonary function and recipient survival after bleomycin-induced lung injury | [176] | |
Mouse iPSCs-derived AT2 cells | Intravenous route. A dose of 5 × 10⁵ cells/mouse 24 h after a single intratracheal bleomycin administration | The animals were euthanized 13 days after bleomycin challenge. Treated mice after bleomycin have decreased collagen deposition and lung inflammation | [179] | |
Human iPSCs-derived AT2 cells | Intratracheal route. A dose of 3 × 106 cells/rat 15 days after a single intratracheal bleomycin administration | The animals were sacrificed 21 days after bleomycin administration. Transplanted lungs showed no inflammation, no edema, no epithelial damage and reduced fibrosis | [182] | |
AT2, AT1 and Club cells derived from human embryonic stem cells (hESCs) | Intratracheal route. A dose of 1 × 10⁵ differentiated hESCs/mouse 7 days after a single intratracheal bleomycin administration and immediately after sublethal irradiation to avoid graft rejection | The animals were euthanized 14 days after bleomycin challenge. Treated mice, after bleomycin instillation, showed an increase in progenitor number in the airways and reduced collagen content | [180] | |
Clinical human studies | AT2 cells (heterologous) | Intratracheal route. A total of 16 IPF patients. Four doses of 1000–1.200 × 106 cells/patient | Enrolled patients were monitored for 1 year. Administered AT2 cells were both safe and well tolerated. There was no deterioration in pulmonary function, respiratory symptoms or disease extent after 12 months of follow-up. This study lacks a control group due to ethical issues | [142] |
SOX9 + BCs (autologous) | Endobronchial route. A total of 2 bronchiectasis patients. A dose of 1 × 106 cells/kg body weight/patient | This study was the first autologous SOX9 + BCs transplantation clinical trial. Lung tissue repair and pulmonary function enhancement was observed in patients 3–12 months after cell transplantation | [186] | |
SOX9 + BCs (autologous) | Endobronchial route. A total of 7 bronchiectasis. A dose of 1 × 106 cells/kg body weight/patient | Enrolled patients were monitored for 1 year. Transplantation of autologous SOX9 + BCs had positive effects and is safe for patients with bronchiectasis | [187] | |
BM-MSCs (allogeneic) | Intravenous route. A total of 20 patients with usual interstitial pneumonia and a history of lung function decline over the last 12 months, among other characteristics. Two doses of 200 × 106 cells/patient, every 3 months | Enrolled patients were monitored for 1 year. This study concluded that therapy with high doses of allogeneic MSCs is a safe and promising method to reduce disease progression in IPF patients with rapid pulmonary function decline | [188] | |
ADSC-SVF (stromal vascular function) | Endobronchial route. A total of 14 IPF patients. A dose of 0.5 × 106 cells/kg body weight/patient/month (a total of 3 months) | Enrolled patients were monitored for 1 year. There was no formation of ectopic tissues and no difference in adverse events compared to placebo effect. Treatment was safe for IPF patients | [189] | |
ADSC-SVF (stromal vascular function) | Endobronchial route. A total of 14 IPF patients. A dose of 0.5 × 106 cells/kg body weight/patient/month (a total of 3 months) | This study is the follow-up of the study above. They saw a significant functional decline was observed at 24 months after the first administration and highlighted the need of further clinical trials using these cells | [190] | |
BM-MSCs (allogeneic) | Intravenous route. A total of 9 IPF patients. A dose of either 20 × 106, 100 × 106 or 200 × 106 cells/patient | Safety was assessed for 15 months in total. No treatment-emergent serious adverse events were reported in this study. This trial (called AETHER) was the first clinical trial conducted for 15 months to assess the safety of a single intravenous infusion of BM-MSCs | [191] | |
Placental MSCs (allogeneic) | Intravenous route. A total of 8 IPF patients. A dose of either 1 × 106 or 2 × 106 cells/kg body weight/patient | Enrolled patients were followed for 6 months. Intravenous administration of these cells was proven to be feasible and to have a good short-term safety profile in patients with moderately severe IPF | [192] | |
BM-MSCs (allogeneic) | Intravenous route. A total of 9 IPF patients. A dose of either 20 × 106, 100 × 106 or 200 × 106 cells/patient | This study is a follow-up of the AETHER trial. The subjects receiving the higher dose demonstrated better results when compared to those receiving the lowest dose | [193] |
4. Current Challenges
5. Future Perspectives and Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Murine Models | Main Pathological Features | Pros | Cons | Ref |
---|---|---|---|---|
Bleomycin (single dose (I.T, I.N, I.V) or repeated doses (I.T, I.N, I.P, O.A, I.V)) | Epithelial cell injury. Fibroblast foci. Macrophage oxidative stress. Fiber deposition | Some of the molecular signatures as well as some histopathological hallmarks at distinct stages of bleomycin-induced lung fibrosis resemble those encountered in human fibrotic lung diseases. Quick development of fibrosis. Relative ease of induction, reproducibility and versatility. Economical | Important role of inflammation in the development of fibrosis. Some reports show that the fibrotic lesions resolved naturally after day 21–28, while other recent studies indicated persistence of fibrosis, albeit with less inflammation as long as 6 months after a single or repetitive bleomycin treatment(s). However, the chronic model that uses several doses of bleomycin may overcome the natural-resolving fibrosis handicap | [45,47,48,49,50,51,52,53,54] |
Silica | Fibrotic nodules develop around silica deposits and silica fibers are easily identified both by histology and polarization microscopy. Macrophage NALP3 inflammasome activation regulates disease development | Development of fibrotic nodules that resemble lesions that develop in humans following exposure to mineral fibers and particulate aerosols. Persistence of fibrotic lesions due to diminished clearance of silica particles from the lungs | Highly expensive and difficult delivery, prolonged waiting periods until fibrosis develops (4–16 weeks), lack of reproducibility of fibrotic pattern, absence of usual interstitial pneumonia (UIP)-like lesions | [48,55] |
Asbestosis | Asbestos bodies embedded within the fibrous tissue, fewer myofibroblasts foci and bronchial wall fibrosis. In some cases, the pattern of UIP can be also present | Recapitulates asbestos exposure in human lung fibrosis | A single intratracheal administration elicits an uneven distribution of fibrosis between lungs which also tends to develop in the core of the lung rather than in the subpleura. The fibrosis developed from the inhalation model is more peripheral but requires at least a month for fibrosis to develop | [55] |
Hyperoxia | Hypoalveolarization. Increased elastin and collagen-I deposition by α-actin-positive myofibroblasts. Increased periostin expression in the alveolar walls, particularly in areas of interstitial thickening | Allows the study of prolonged exposure to supplemental oxygen | Additional studies investigating controversial molecular mechanisms underlying hyperoxia-induced cell injury should be performed since these may be helpful in future pharmaceutical interventions | [56,57] |
Acid instillation | Pattern of fibrosis involves interstitial rather than alveolar consolidation | Allows studies of hypoxemia, permeability injuries and effects of hyperoxia. It also models fibroproliferative changes seen with ALI and ARDS | Modifications (e.g., a fluid bolus, supplemental oxygen and careful monitoring to be assured of surviving the procedure) are imperative because without them the animals die of lung injury before the development of lung scarring | [48] |
Cytokine overexpression | Epithelial apoptosis and myofibroblast accumulation. Airway and parenchymal fibrotic response | Ability to dissect downstream signaling events relevant to specific fibrotic-inducing cytokines. Fibrotic scarring tends to be more persistent in some models than those produced by bleomycin | Models limited to dissecting specific pathways. Highly variable and heterogeneous kinetics of injury regarding severity, lesions extension and lack of reproducibility | [55] |
Fluorescent isothiocyanate (FITC) | AEC injury. Vascular leak | Relatively reproducible and persistent fibrotic phenotypes. Easily trackable fluorescence-labeled fibrotic tissues | Lack representative UIP and inflammatory infiltrates preceding fibrosis. Technical issues regarding FITC particles may compromise model robustness. Limited human relevance since this type of injurious stimulus has never been described in humans | [48,55] |
Radiation-induced | AEC injury. Vascular remodeling. MSCs regulate repair responses | Results in fibrosis and can be local or systemic if other organs are not shielded | Fibrosis takes a long time to develop. Mainly dependent on inflammation and free-radical-mediated DNA damage and less on TFG-B | [48,55] |
Familial models | Depends on the altered gene of study | Useful to study the disease genetic background | Mutations may produce a susceptible phenotype, requiring also a second hit from environmental origin to partially recapitulate the human phenotype | [55] |
Humanized (NOD/SCID mice) | Immunodeficient mice | It allows for cell trafficking during different stages of fibrosis development and progression, offers insights into role of different fibroblast populations and dissects the contribution of epithelial-fibroblast crosstalk in the absence of immune cells | May not be representative of human disease where immune cells play a role. High cost and requires specialized housing. | [55] |
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Egea-Zorrilla, A.; Vera, L.; Saez, B.; Pardo-Saganta, A. Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis. Cells 2022, 11, 2595. https://doi.org/10.3390/cells11162595
Egea-Zorrilla A, Vera L, Saez B, Pardo-Saganta A. Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis. Cells. 2022; 11(16):2595. https://doi.org/10.3390/cells11162595
Chicago/Turabian StyleEgea-Zorrilla, Alejandro, Laura Vera, Borja Saez, and Ana Pardo-Saganta. 2022. "Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis" Cells 11, no. 16: 2595. https://doi.org/10.3390/cells11162595
APA StyleEgea-Zorrilla, A., Vera, L., Saez, B., & Pardo-Saganta, A. (2022). Promises and Challenges of Cell-Based Therapies to Promote Lung Regeneration in Idiopathic Pulmonary Fibrosis. Cells, 11(16), 2595. https://doi.org/10.3390/cells11162595