Remember Me? The Bone Marrow in Pulmonary Fibrosis.
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ABSTRACT:
SUBMITTER: Rangarajan S
PROVIDER: S-EPMC6794115 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The origin of fibroblasts in pulmonary fibrosis is assumed to be intrapulmonary, but their extrapulmonary origin and especially derivation from bone marrow (BM) progenitor cells has not been ruled out. To examine this possibility directly, adult mice were durably engrafted with BM isolated from transgenic mice expressing enhanced GFP. Induction of pulmonary fibrosis in such chimera mice by endotracheal bleomycin (BLM) injection caused large numbers of GFP(+) cells to appear in active fibrotic lesions, while only a few GFP(+) cells could be identified in control lungs. Flow-cytometric analysis of lung cells confirmed the BLM-induced increase in GFP(+) cells in chimera mice and revealed a significant increase in GFP(+) cells that also express type I collagen. GFP(+) lung fibroblasts isolated from chimera mice expressed collagen and telomerase reverse transcriptase but not alpha-smooth muscle actin. Treatment of isolated GFP(+) fibroblasts with TGF-beta failed to induce myofibroblast differentiation. Cultured lung fibroblasts expressed the chemokine receptors CXCR4 and CCR7 and responded chemotactically to their cognate ligands, stromal cell-derived factor-1 alpha and secondary lymphoid chemokine, respectively. Thus the collagen-producing lung fibroblasts in pulmonary fibrosis can also be derived from BM progenitor cells.
| S-EPMC310750 | biostudies-literature
Project description:Mutations in the essential telomerase components hTERT and hTR cause dyskeratosis congenita, a bone marrow failure syndrome characterized by mucocutaneous features. Some (~ 3%) sporadic aplastic anemia (AA) and idiopathic pulmonary fibrosis cases also carry mutations in hTERT and hTR. Even though it can affect clinical outcome, because the mutation frequency is rare, genetic testing is not standard. We examined whether the cooccurrence of bone marrow failure and pulmonary fibrosis in the same individual or family enriches for the presence of a telomerase mutation. Ten consecutive individuals with a total of 36 family members who fulfilled these criteria carried a germline mutant telomerase gene (100%). The mean age of onset for individuals with AA was significantly younger than that for those with pulmonary fibrosis (14 vs 51; P < .0001). Families displayed autosomal dominant inheritance and there was an evolving pattern of genetic anticipation, with the older generation primarily affected by pulmonary fibrosis and successive generations by bone marrow failure. The cooccurrence of AA and pulmonary fibrosis in a single patient or family is highly predictive for the presence of a germline telomerase defect. This diagnosis affects the choice of bone marrow transplantation preparative regimen and can prevent morbidity.
| S-EPMC3110022 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic lung disease for which age is the most important risk factor. Different mechanisms associated with aging, including stem cell dysfunction, have been described to participate in the pathophysiology of IPF. We observed an extrapulmonary effect associated with IPF: increase in cell senescence of bone marrow-derived mesenchymal stem cells (B-MSCs).MethodsB-MSCs were obtained from vertebral bodies procured from IPF patients and age-matched normal controls. Cell senescence was determined by cell proliferation and expression of markers of cell senescence p16INK4A, p21, and β-galactosidase activity. Mitochondrial function and DNA damage were measured. Paracrine induction of senescence and profibrotic responses were analyzed in vitro using human lung fibroblasts. The reparative capacity of B-MSCs was examined in vivo using the bleomycin-induced lung fibrosis model.ResultsIn our study, we demonstrate for the first time that B-MSCs from IPF patients are senescent with significant differences in mitochondrial function, with accumulation of DNA damage resulting in defects in critical cell functions when compared with age-matched controls. Senescent IPF B-MSCs have the capability of paracrine senescence by inducing senescence in normal-aged fibroblasts, suggesting a possible link between senescent B-MSCs and the late onset of the disease. IPF B-MSCs also showed a diminished capacity to migrate and were less effective in preventing fibrotic changes observed in mice after bleomycin-induced injury, increasing illness severity and proinflammatory responses.ConclusionsWe describe extrapulmonary alterations in B-MSCs from IPF patients. The consequences of having senescent B-MSCs are not completely understood, but the decrease in their ability to respond to normal activation and the risk of having a negative impact on the local niche by inducing inflammation and senescence in the neighboring cells suggests a new link between B-MSC and the onset of the disease.
| S-EPMC6158816 | biostudies-literature
Project description:BackgroundSilicosis is a common occupational disease, characterized by silicotic nodules and diffuse pulmonary fibrosis. We demonstrated an anti-fibrotic effect of bone marrow mesenchymal stem cells (BMSCs) in silica-induced lung fibrosis. In the present study, we sought to clarify the homing ability of BMSCs and the specific mechanisms for their effects.Methods and resultsThe biodistribution of BMSCs was identified by near-infrared fluorescence (NIRF) imaging in vivo and in vitro. The results showed that BMSCs labeled with NIR-DiR dyes targeted silica-injured lung tissue, wherein they reached a peak at 6?h post-injection and declined dramatically by day 3. Based on these findings, a second injection of BMSCs was administered 3?days after the first injection. The injected BMSCs migrated to the injured lungs, but did not undergo transformation into specific lung cell types. Interestingly, the injection of BMSC-conditioned medium (BMSCs-CM) significantly attenuated silica-induced pulmonary fibrosis. The collagen deposition and number of nodules were decreased in lung tissues of BMSCs-CM-treated rats. In parallel with these findings, the mRNA levels of collagen I, collagen III, and fibronectin, and the content of transforming growth factor (TGF)-?1 and hydroxyproline were decreased in the BMSCs-CM-treated group compared with the silica group. In addition, alveolar epithelial markers were upregulated by BMSCs-CM treatment.ConclusionsBMSCs migrated to injured areas of the lung after silica instillation and attenuated pulmonary fibrosis. The anti-fibrotic effects of BMSCs were mainly exerted in paracrine manner, rather than through their ability to undergo differentiation.
| S-EPMC6280342 | biostudies-literature
Project description:RationaleIdiopathic pulmonary fibrosis (IPF) has a dismal prognosis. Mesenchymal stromal cells (MSCs) have shown benefit in other inflammatory diseases.ObjectivesTo evaluate the safety and feasibility of endobronchial administration of bone marrow autologous MSCs (BM-MSC) in patients with mild-to-moderate IPF.MethodsA phase I multicentre clinical trial (ClinicalTrials.gov NCT01919827) with a single endobronchial administration of autologous adult BM-MSCs in patients diagnosed with mild-to-moderate IPF. In a first escalating-dose phase, three patients were included sequentially in three dose cohorts (10×106, 50×106 and 100×106 cells). In a second phase, nine patients received the highest tolerated dose. Follow-up with pulmonary function testing, 6-min walk test and St George's Respiratory Questionnaire was done at 1, 2, 3, 6 and 12 months, and with computed tomography at 3, 6 and 12 months.Results21 bone marrow samples were obtained from 17 patients. Three patients were excluded from treatment due to chromosome aberrations detected in MSCs after culture, and one patient died before treatment. Finally, 13 patients received the BM-MSC infusion. No treatment-related severe adverse events were observed during follow-up. Compared to baseline, the mean forced vital capacity showed an initial decline of 8.1% at 3 months. The number of patients without functional progression was six (46%) at 3 months and three (23%) at 12 months.ConclusionsThe endobronchial infusion of BM-MSCs did not cause immediate serious adverse events in IPF patients, but a relevant proportion of patients suffered clinical and/or functional progression. Genomic instability of BM-MSCs during culture found in three patients may be troublesome for the use of autologous MSCs in IPF patients.
| S-EPMC8236617 | biostudies-literature
Project description:Rationale: The impact of lung insult on the bone marrow (BM) and subsequent disease is unknown.Objectives: To study alterations in the BM in response to lung injury/fibrosis and examine their impact on subsequent lung insult.Methods: BM cells from control or bleomycin-treated donor mice were transplanted into naive mice, which were subsequently evaluated for bleomycin-induced pulmonary fibrosis. In addition, the effect of prior bleomycin treatment on subsequent fibrosis was examined in wild-type and B7H3-knockout mice. Samples from patients with idiopathic pulmonary fibrosis were analyzed for potential clinical relevance of the findings.Measurements and Main Results: Recipient mice transplanted with BM from bleomycin-pretreated donors showed significant exacerbation of subsequent fibrosis with increased B7H3+ cell numbers and a T-helper cell type 2-skewed phenotype. Pretreatment with a minimally fibrogenic/nonfibrogenic dose of bleomycin also caused exacerbation, but not in B7H3-deficient mice. Exacerbation was not observed if the mice received naive BM cell transplant after the initial bleomycin pretreatment. Soluble B7H3 stimulated BM Ly6Chi monocytic cell expansion in vitro and caused similar expansion in the lung in vivo. Notably, soluble B7H3 was elevated in plasma of patients with idiopathic pulmonary fibrosis and in BAL fluid in those with acute exacerbation. Finally, ST2 deficiency diminished the bleomycin-induced B7H3 and IL-13 upregulation, suggesting a role for type 2 innate lymphoid cells.Conclusions: Pulmonary fibrosis caused significant alterations in BM with expansion and activation of monocytic cells, which enhanced fibrosis when transplanted to naive recipients with potential mediation by a novel role for B7H3 in the pathophysiology of pulmonary fibrosis in both mice and humans.
| S-EPMC6794107 | biostudies-literature
Project description:Many common diseases of the gas exchange surface of the lung have no specific treatment but cause serious morbidity and mortality. Idiopathic Pulmonary Fibrosis (IPF) is characterized by alveolar epithelial cell injury, interstitial inflammation, fibroblast proliferation and collagen accumulation within the lung parenchyma. Keratinocyte Growth Factor (KGF, also known as FGF-7) is a critical mediator of pulmonary epithelial repair through stimulation of epithelial cell proliferation. During repair, the lung not only uses resident cells after injury but also recruits circulating bone marrow-derived cells (BMDC). Several groups have used Mesenchymal Stromal Cells (MSCs) as therapeutic vectors, but little is known about the potential of Hematopoietic Stem cells (HSCs). Using an inducible lentiviral vector (Tet-On) expressing KGF, we were able to efficiently transduce both MSCs and HSCs, and demonstrated that KGF expression is induced in a regulated manner both in vitro and in vivo. We used the in vivo bleomycin-induced lung fibrosis model to assess the potential therapeutic effect of MSCs and HSCs. While both populations reduced the collagen accumulation associated with bleomycin-induced lung fibrosis, only transplantation of transduced HSCs greatly attenuated the histological damage. Using double immunohistochemistry, we show that the reduced lung damage likely occurs through endogenous type II pneumocyte proliferation induced by KGF. Taken together, our data indicates that bone marrow transplantation of lentivirus-transduced HSCs can attenuate lung damage, and shows for the first time the potential of using an inducible Tet-On system for cell based gene therapy in the lung.
| S-EPMC2779453 | biostudies-literature
Project description:BackgroundPulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. Previous studies have shown that early intervention with bone marrow mesenchymal stem/stromal cells (BMSCs) has positive effect on anti-pulmonary fibrosis caused by silica dust. However, early intervention using BMSCs is not practical, and the therapeutic effects of BMSCs advanced intervention on pulmonary fibrosis have rarely been reported. In this study, we investigated the effects of advanced transplantation (on the 28th day after exposure to silica suspension) of BMSCs on an established rat model of pulmonary fibrosis.MethodsSprague Dawley (SD) rats were randomly divided into four groups including (1) control group (n = 6) which were normally fed, (2) silica model group (n = 6) which were exposed to silica suspension (1 mL of 50 mg/mL/rat), (3) BMSC transplantation group (n = 6) which received 1 mL BMSC suspension (2 × 106 cells/mL) by tail vein injection on the 28th day after exposure to silica suspension, and (4) BMSC-CM (conditioned medium) transplantation group (n = 6) which received CM from the same cell number by tail vein injection on the 28th day after exposure to silica suspension. On the 56th day after exposure to silica suspension, we used computed tomography (CT), hematoxylin and eosin (H&E), and Masson's trichrome staining to evaluate the changes in lung tissue. We examined the expression of epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related proteins in lung tissue using immunohistochemistry and western blotting.ResultsSuccessful construction of a pulmonary fibrosis model was confirmed by H&E and Masson's trichrome staining on the 28th day after exposure to silica suspension. On the 56th day after exposure, pulmonary CT examination showed a relieving effect of BMSCs on silica-induced pulmonary fibrosis which was confirmed by H&E and Masson's trichrome staining. Treatment of BMSCs increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including Vimentin (Vim) and α-Smooth actin (α-SMA) after exposure to silica suspension. Furthermore, we found that Wnt/β-catenin signaling pathway is abnormally activated in silica-induced pulmonary fibrosis, and exogenous transplantation of BMSCs may attenuate their expression.ConclusionsBMSC transplantation inhibits the EMT to alleviate silica-induced pulmonary fibrosis in rats and the anti-fibrotic effect potentially by attenuating Wnt/β-catenin signaling. ᅟ: ᅟ.
| S-EPMC6234553 | biostudies-literature
Project description:Understanding the role of CXCL4 in the initiation and progression of bone marrow fibrosis
| PRJEB39607 | ENA
Project description:Bone marrow fibrosis is a central pathological feature and World Health Organization major diagnostic criterion of myelofibrosis. Although bone marrow fibrosis is seen in a variety of malignant and non-malignant disease states, the deposition of reticulin and collagen fibrosis in the bone marrow of patients with myelofibrosis is believed to be mediated by the myelofibrosis hematopoietic stem/progenitor cell, contributing to an impaired microenvironment favoring malignant over normal hematopoiesis. Increased expression of inflammatory cytokines, lysyl oxidase, transforming growth factor-β, impaired megakaryocyte function, and aberrant JAK-STAT signaling have all been implicated in the pathogenesis of bone marrow fibrosis. A number of studies indicate that bone marrow fibrosis is an adverse prognostic variable in myeloproliferative neoplasms. However, modern myelofibrosis prognostication systems utilized in risk-adapted treatment approaches do not include bone marrow fibrosis as a prognostic variable. The specific effect on bone marrow fibrosis of JAK2 inhibition, and other rationally based therapies currently being evaluated in myelofibrosis, has yet to be fully elucidated. Hematopoietic stem cell transplantation remains the only curative therapeutic approach that reliably results in resolution of bone marrow fibrosis in patients with myelofibrosis. Here we review the pathogenesis, biological consequences, and prognostic impact of bone marrow fibrosis. We discuss the rationale of various anti-fibrogenic treatment strategies targeting the clonal hematopoietic stem/progenitor cell, aberrant signaling pathways, fibrogenic cytokines, and the tumor microenvironment.
| S-EPMC5013940 | biostudies-literature