Airway delivery of soluble factors from plastic-adherent bone marrow cells prevents murine asthma.

m J Respir Cell Mol Biol. 2012 Feb;46(2):207-16. Epub 2011 Sep 8.
Airway delivery of soluble factors from plastic-adherent bone marrow cells prevents murine asthma.
Ionescu LI, Alphonse RS, Arizmendi N, Morgan B, Abel M, Eaton F, Duszyk M, Vliagoftis H, Aprahamian TR, Walsh K, Thébaud B.
Source
University of Alberta, HMRC 407, Edmonton, AB, Canada.
Abstract
Asthma affects an estimated 300 million people worldwide and accounts for 1 of 250 deaths and 15 million disability-adjusted life years lost annually. Plastic-adherent bone marrow-derived cell (BMC) administration holds therapeutic promise in regenerative medicine. However, given the low cell engraftment in target organs, including the lung, cell replacement cannot solely account for the reported therapeutic benefits. This suggests that BMCs may act by secreting soluble factors. BMCs also possess antiinflammatory and immunomodulatory properties and may therefore be beneficial for asthma. Our objective was to investigate the therapeutic potential of BMC-secreted factors in murine asthma. In a model of acute and chronic asthma, intranasal instillation of BMC conditioned medium (CdM) prevented airway hyperresponsiveness (AHR) and inflammation. In the chronic asthma model, CdM prevented airway smooth muscle thickening and peribronchial inflammation while restoring blunted salbutamol-induced bronchodilation. CdM reduced lung levels of the T(H)2 inflammatory cytokines IL-4 and IL-13 and increased levels of IL-10. CdM up-regulated an IL-10-induced and IL-10-secreting subset of T regulatory lymphocytes and promoted IL-10 expression by lung macrophages. Adiponectin (APN), an antiinflammatory adipokine found in CdM, prevented AHR, airway smooth muscle thickening, and peribronchial inflammation, whereas the effect of CdM in which APN was neutralized or from APN knock-out mice was attenuated compared with wild-type CdM. Our study provides evidence that BMC-derived soluble factors prevent murine asthma and suggests APN as one of the protective factors. Further identification of BMC-derived factors may hold promise for novel approaches in the treatment of asthma.
PMID: 21903873
[PubMed – indexed for MEDLINE]

Curr Stem Cell Res Ther. 2010 Jun;5(2):111-5.
Immunomodulatory effects of adipose-derived stem cells in airway allergic diseases.
Cho KS, Roh HJ.
Source
Department of ORL-HNS and Medical Research Institute, Pusan National University School of Medicine, Busan, South Korea.
Abstract
Allergic rhinitis and asthma are inflammatory airway allergic diseases caused by Th2-driven immune response. Several studies have shown that multipotent adipose-derived stem cells (ASCs) can exert profound immunosuppressive effects via modulation of both cellular and innate immune pathway, especially immunosuppressive effect on T cell activities. ASCs’ ability to be readily isolated from a number of adipose tissues and expanded ex vivo makes them attractive candidate for use in clinical therapy in the context of allogeneic transplantation, in particular to modulate graft-versus-host disease and graft rejection. The authors have investigated whether ASCs can inhibit Th2-dependent airway allergic disease in the mouse model. In this article we review recent experimental data and discuss about the mechanisms by which ASCs inhibit allergic airway inflammation via immunomodulation from a Th2 to a Th1-biased response in the mouse model.
PMID:
19941459
[PubMed – indexed for MEDLINE] Br Med Bull. 2011 Jun 7. [Epub ahead of print] The use of stem cells to repair the injured lung.
Polak DJ.
Source
Faculty of Medicine, Room 144, Roderic Hill Building at the Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
Abstract
Introduction The structure of the lung is complex, it contains at least 40 different cell types. The lung interacts with the outside environment and the circulatory system. These features make the lung particularly susceptible to injury and disease. Areas of agreement Stem cells with reparative properties can be found within the lung. Also, outside sources of stem cells can contribute to the repair of the injured lung. These include multipotent stem cells from the bone marrow and pluripotent stem cells derived from the early embryo or from adult cells, which are made to reverse to a pluripotent state by the addition of viral vectors or non-viral agents. For stem cells of outside sources to have a reparative function, the cells need to reach the injured lung, either by internal mobilization of stem cells from other parts of the body (e.g. bone marrow) or by administration of exogenous cell sources. Areas of controversy Much research is currently undertaken to define the mechanisms by which stem cells repair the injured tissue. These include the possibility of engraftment of exogenous cells or the release of growth factors from the cells to aid repair. There is not as yet a clear consensus as to the mechanisms of repair. Current research and timelines Interest is now focused on developing appropriate animal models to test the safety and efficacy of stem cell therapies and to understand the mechanisms by which stem cells undertake this task.
PMID:
21652592
[PubMed – as supplied by publisher] Respirology. 2011 Feb;16(2):223-37. doi: 10.1111/j.1440-1843.2010.01914.x.
Cellular therapies for lung disease: a distant horizon.
Moodley Y, Manuelpillai U, Weiss DJ.
Source
School of Medicine and Pharmacology, University of Western Australia, Royal Perth Hospital, Perth, Western Australia, Australia. yuben.moodley@uwa.edu.au
Abstract
Lung diseases constitute a major global burden of health and are characterized by inflammation and chronic fibrosis resulting in a loss of gas exchange units. To date there has been no effective treatment to reverse these chronic inflammatory changes and tissue remodelling. Recently, stem cells have been shown to successfully treat animal models of lung disease. In addition, certain cells have demonstrated a capacity to differentiate into lung cells. Based on these preliminary data, there are clinical trials underway to examine the potential for cellular therapies in lung disease. Recently, there have been a variety of cell examined for both their immunomodulatory effects on the lung as well as their potential for differentiation into lung cells. These range from lung progenitor cells, circulating cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPS), placental stem cells and embryonic stem cells (ESCs). Several cell types demonstrate immunomodulatory effects including circulating cells, MSCs and placental stem cells. In addition, iPS, placental cells and ESCs have shown some capacity for differentiation. Despite these major steps forward cellular therapy for lung diseases still faces challenges. Issues that need to be resolved include bioethical issues, the safety of cell transplantation, ideal routes of delivery, the timing and the specific indications that would make cellular therapy effective.
© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.
PMID:
21199158
[PubMed – indexed for MEDLINE]

Am J Physiol Lung Cell Mol Physiol. 2010 Dec;299(6):L760-70. Epub 2010 Sep 3.
Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model.
Bonfield TL, Koloze M, Lennon DP, Zuchowski B, Yang SE, Caplan AI.
Source
Dept. of Pediatrics, Case Western Reserve Univ., Cleveland, OH 44106-4948, USA. tracey.bonfield@case.edu
Abstract
Allogeneic human mesenchymal stem cells (hMSCs) introduced intravenously can have profound anti-inflammatory activity resulting in suppression of graft vs. host disease as well as regenerative events in the case of stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of these diseases. hMSCs produce bioactive factors that provide molecular cuing for: 1) immunosuppression of T cells; 2) antiscarring; 3) angiogenesis; 4) antiapoptosis; and 5) regeneration (i.e., mitotic for host-derived progenitor cells). Studies have shown that hMSCs have profound effects on the immune system and are well-tolerated and therapeutically active in immunocompetent rodent models of multiple sclerosis and stroke. Furthermore, intravenous administration of MSCs results in pulmonary localization. Asthma is a major debilitating pulmonary disease that impacts in excess of 150 million people in the world with uncontrolled asthma potentially leading to death. In addition, the socioeconomic impact of asthma-associated illnesses at the pediatric and adult level are in the millions of dollars in healthcare costs and lost days of work. hMSCs may provide a viable multiaction therapeutic for this inflammatory lung disease by secreting bioactive factors or directing cellular activity. Our studies show the effectiveness and specificity of the hMSCs on decreasing chronic airway inflammation associated with the murine ovalbumin model of asthma. In addition, the results from these studies verify the in vivo immunoeffectiveness of hMSCs in rodents and support the potential therapeutic use of hMSCs for the treatment of airway inflammation associated with chronic asthma.
PMID:
20817776
[PubMed – indexed for MEDLINE] Panminerva Med. 2009 Mar;51(1):5-16.
Mesenchymal stem cells and inflammatory lung diseases.
Iyer SS, Co C, Rojas M.
Source
Division of Pulmonary, Allergy and Critical Care Medicine, Emory University, Atlanta, GA 30322, USA.
Abstract
Mesenchymal stem cells (MSCs) are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized Phase I/II clinical trials are evaluating the effects of allogeneic MSC infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn’s disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this Review, we describe how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. We also address potential pitfalls related to the therapeutic use of MSCs in fibrotic lung diseases such as idiopathic pulmonary fibrosis. In addition, we identify emerging areas for MSC- based therapies in modulating oxidative stress and in attenuating inflammation in alcohol-related acute lung injury.
PMID:
19352305
[PubMed – indexed for MEDLINE] Ther Adv Respir Dis. 2008 Jun;2(3):173-7.
Stem cell therapy: the great promise in lung disease.
Siniscalco D, Sullo N, Maione S, Rossi F, D’Agostino B.
Source
Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, via S. Maria di Costantinopoli, 16-80138 Napoli, Italy. dariosin@uab.edu
Abstract
Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.
PMID:
19124369
[PubMed – indexed for MEDLINE] Transplant Proc. 2008 Jun;40(5):1700-5.
Therapeutic effects of bone marrow-derived mesenchymal stem cells engraftment on bleomycin-induced lung injury in rats.
Zhao F, Zhang YF, Liu YG, Zhou JJ, Li ZK, Wu CG, Qi HW.
Source
Department of Respiratory, Xijing Hospital, Xi’an, China.
Abstract
Previous studies have demonstrated that bone marrow-derived mesenchymal stem cell (MSC) engraftment attenuated lung injury in a model induced by bleomycin in mice. However, the mechanisms are not completely understood. The primary objective of the present study was to determine whether MSC engraftment can also protect lungs against bleomycin-induced injury in rats and to observe any beneficial effects of cytokines. Twelve hours after bleomycin (5 mg/kg) or phosphate-buffered saline was perfused into the trachea, 5×10(6) DAPI-labeled MSCs or DMEM-F12 were injected into the tail vein of rats. Two weeks later, MSCs labeled with DAPI were detected by pan-cytokeratin staining. The level of laminin and hyaluronan in bronchoalveolar lavage fluid was measured by radioimmunoassay. Collagen content in lung tissue was calculated by the hydroxyproline assay. TGF-beta1, PDGF-A, B, and IGF-I were measured by real-time PCR. It was observed that some MSCs positive for pan-cytokeratin staining, an indicator of alveolar epithelial cells, were present in injured lung tissue. Bleomycin injection increased the content of hydroxyproline in lung tissue, as well as laminin and hyaluronan in bronchoalveolar lavage fluid, markers for lung injury and fibrosis. However, these effects were attenuated by MSC treatment. Furthermore, the increased mRNA levels of TGF-beta1, PDGF-A, PDGF-B, and IGF-I following bleomycin injection were also significantly decreased by MSC treatment. These observations provided evidence that MSCs are still present in the lung 2 weeks after the initial MSC treatment in rats, as well as documented the beneficial effects of MSC engraftment against bleomycin-induced lung injury associated with changes in TGF-beta1, PDGF-A, PDGF-B, and IGF-I. These results may provide an experimental base for clinical therapy of pulmonary fibrosis in the future.
PMID:
18589176
[PubMed – indexed for MEDLINE] Stem Cells. 2011 May 4. doi: 10.1002/stem.656. [Epub ahead of print] Bone Marrow Derived Mesenchymal Stromal Cells Inhibit Th2-Mediated Allergic Airways Inflammation in Mice.
Goodwin M, Sueblinvong V, Eisenhauer P, Ziats NP, Leclair L, Poynter ME, Steele C, Rincon M, Weiss DJ.
Source
Department of Medicine, University of Vermont College of Medicine, Burlington VT 05405; Department of Pathology, Case Western Reserve University, Cleveland OH 44106; Department of Medicine, University of Alabama at Birmingham, Birmingham AL 35294.
Abstract
Bone marrow-derived mesenchymal stromal cells (BMSCs) mitigate inflammation in mouse models of acute lung injury. However, specific mechanisms of BMSC actions on CD4 T lymphocyte-mediated inflammation in vivo remain poorly understood. Limited data suggests promotion of Th2 phenotype in models of Th1-mediated diseases. However whether this might alleviate or worsen Th2-mediated diseases such as allergic asthma is unknown. To ascertain the effects of systemic administration of BMSCs in a mouse model of Th2-mediated allergic airways inflammation, ovalbumin-induced allergic airways inflammation was induced in wild type C57BL/6 and BALB/c mice as well as in IFNγ receptor null mice. Effects of systemic administration during antigen sensitization of either syngeneic or allogeneic BMSC on airways hyper-reactivity, lung inflammation, antigen-specific CD4 T lymphocytes, and serum immunoglobulins were assessed. Both syngeneic and allogeneic BMSCs inhibited airways hyper-reactivity and lung inflammation through a mechanism partly dependent on IFNγ. However, contrary to existing data, BMSCs did not affect antigen-specific CD4 T lymphocyte proliferation but rather promoted Th1 phenotype in vivo as assessed by both ova-specific CD4 T lymphocyte cytokine production and ova-specific circulating immunoglobulins. BMSCs treated to prevent release of soluble mediators and a control cell population of primary dermal skin fibroblasts only partly mimicked the BMSC effects and in some cases worsened inflammation. In conclusion, BMSCs inhibit Th2-mediated allergic airways inflammation by influencing antigen-specific CD4 T lymphocyte differentiation. Promotion of a Th1 phenotype in antigen-specific CD4 T lymphocytes by BMSCs is sufficient to inhibit Th2-mediated allergic airways inflammation through an IFNγ-dependent process.
Copyright © 2011 AlphaMed Press.
PMID:
21544902
[PubMed – as supplied by publisher] Int Immunopharmacol. 2011 Mar 23. [Epub ahead of print] Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma.
Firinci F, Karaman M, Baran Y, Bagriyanik A, Ayyildiz ZA, Kiray M, Kozanoglu I, Yilmaz O, Uzuner N, Karaman O.
Source
Pediatric Allergy and Immunology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
Abstract
Asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. Mesenchymal stem cells (MSCs) are promising for the development of novel therapies in regenerative medicine. This study aimed to examine the efficacy of MSCs on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: Group 1 (control group, n=6), Group 2 (ovalbumin induced asthma only, n=10), Group 3 (ovalbumin induced asthma + MSCs, n=10), and Group 4 (MSCs only, n=10). Histological findings (basement membrane, epithelium, subepithelial smooth muscle thickness, numbers of goblet and mast cells) of the airways and MSC migration were evaluated by light, electron, and confocal microscopes. In Group 3, all early histopathological changes except epithelial thickness and all of the chronic changes were significantly ameliorated when compared with Group 2. Evaluation with confocal microscopy showed that no noteworthy amount of MSCs were present in the lung tissues of Group 4 while significant amount of MSCs was detected in Group 3. Serum NO levels in Group 3, were significantly lower than Group 2. The results of this study revealed that MSCs migrated to lung tissue and ameliorated bronchial asthma in murine model. Further studies are needed to evaluate the efficacy of MSCs for the treatment of asthma.
Copyright © 2011 Elsevier B.V. All rights reserved.
PMID:
21439399
[PubMed – as supplied by publisher] Expert Rev Respir Med. 2010 Dec;4(6):747-58.
Mesenchymal stem cells for repair of the airway epithelium in asthma.
Knight DA, Rossi FM, Hackett TL.
Source
Providence Heart and Lung Institute at St Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada. darryl.knight@hli.ubc.ca
Abstract
The airway epithelium is constantly faced with inflammatory and potentially injurious stimuli. Following damage, rapid repair mechanisms involving proliferation and differentiation of resident progenitor and stem cell pools are necessary in order to maintain a protective barrier. In asthma, evidence pointing to a compromised ability of the epithelium to properly repair and regenerate is rapidly accumulating. The consequences of this are presently unknown but are likely to have a significant impact on lung function. Mesenchymal stem cells have the potential to serve as a universal source for replacement of specific cells in several diseases and thus offer hope as a potential therapeutic intervention for the treatment of the chronic remodeling changes that occur in the asthmatic epithelium. However, controversy exists regarding whether these cells can actually home to and engraft within the airways and contribute to tissue function or whether this mechanism is necessary, since they can have potent paracrine immunomodulatory effects. This article focuses on the current knowledge about specific stem cell populations that may contribute to airway epithelial regeneration and discusses the use of mesenchymal stem cells as a potential therapeutic intervention.
PMID:
21128750
[PubMed – indexed for MEDLINE] Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5652-7. Epub 2010 Mar 15.
Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma.
Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, Hodges MG, Jelinek I, Madala S, Karpati S, Mezey E.
Source
National Institute of Dental and Craniofacial Research, Craniofacial and Skeletal Diseases Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Erratum in
• Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):8041. Gorham, Jared D [corrected to Gorham, James D]; Bundoc, Victor G [corrected to Bundoc, Virgilio G].
Abstract
Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions–specifically therapy resistant asthma–might also be a likely target of the recently discovered cellular therapy approach using BMSCs.
PMID:
20231466
[PubMed – indexed for MEDLINE] PMCID: PMC2851758
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Am J Respir Crit Care Med. 2011 Jan 15;183(2):215-25. Epub 2010 Aug 13.
Adipose stem cell therapy in mice attenuates lung and systemic injury induced by cigarette smoking.
Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S, Traktuev DO, Feng D, Adamowicz JJ, Van Demark M, Fisher AJ, Kamocki K, Brown MB, Presson RG Jr, Broxmeyer HE, March KL, Petrache I.
Source
Division of Pulmonary and Critical Care Medicine, Indiana University, Indianapolis, IN 46202-5120, USA.
Abstract
RATIONALE:
Adipose-derived stem cells express multiple growth factors that inhibit endothelial cell apoptosis, and demonstrate substantial pulmonary trapping after intravascular delivery.
OBJECTIVES:
We hypothesized that adipose stem cells would ameliorate chronic lung injury associated with endothelial cell apoptosis, such as that occurring in emphysema.
METHODS:
Therapeutic effects of systemically delivered human or mouse adult adipose stem cells were evaluated in murine models of emphysema induced by chronic exposure to cigarette smoke or by inhibition of vascular endothelial growth factor receptors.
MEASUREMENTS AND MAIN RESULTS:
Adipose stem cells were detectable in the parenchyma and large airways of lungs up to 21 days after injection. Adipose stem cell therapy was associated with reduced inflammatory infiltration in response to cigarette smoke exposure, and markedly decreased lung cell death and airspace enlargement in both models of emphysema. Remarkably, therapeutic results of adipose stem cells extended beyond lung protection by rescuing the suppressive effects of cigarette smoke on bone marrow hematopoietic progenitor cell function, and by restoring weight loss sustained by mice during cigarette smoke exposure. Pulmonary vascular protective effects of adipose stem cells were recapitulated by application of cell-free conditioned medium, which improved lung endothelial cell repair and recovery in a wound injury repair model and antagonized effects of cigarette smoke in vitro.
CONCLUSIONS:
These results suggest a useful therapeutic effect of adipose stem cells on both lung and systemic injury induced by cigarette smoke, and implicate a lung vascular protective function of adipose stem cell derived paracrine factors.
PMID:
20709815
[PubMed – indexed for MEDLINE]