Asthma
 

     Asthma is a common chronic inflammatory disease of the airways characterized by symptoms including wheezing, coughing, chest tightness, and shortness of breath, reversible airflow obstruction, and bronchospasm. Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in 1 second (FEV1), and peak expiratory flow rate. Asthma may also be classified as atopic (extrinsic) or non-atopic (intrinsic). It can be exercised induced or occupational. Asthma affects an estimated 300 million people worldwide and caused 250,000 deaths in 2009. Traditional management usually focuses on reduction to allergen exposure and medical therapy that consists of beta-2-agonists, anti-cholinergics, or inhaled corticosteroids.

     Research has been ongoing around the world that exploits the anti-inflammatory and immuno-modulatory properties of adult stem cells to control the reactive airways associated with asthma. Our company is investigating the effects of SVF (rich in mesenchymal stem cells and growth factors) on chronic asthma. We use a protocol that includes a combination of intravenous and nebulized SVF delivery. The deployment protocol performed under local anesthesia is all done as an outpatient at the time of SVF harvesting and procurement. The entire cellular surgical procedure takes approximately 3 hours.

 
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RESOURCES

Cell Surgical Network Study for Stromal Vascular Fraction Registered by ClinicalTrials.gov

Rancho Mirage, CA (PRWEB) October 14, 2013

Clinicaltrials.gov, a service of the U.S. National Institutes of Health has registered on their public site an IRB approved safety study from the Cell Surgical Network, Inc.. This study is available for patients with various degenerative and inflammatory conditions to undergo Stromal Vascular Fraction deployment for the evaluation and for the advancement of future stem cell therapy procedures. Stromal Vascular Fraction is rich in autologous adipose derived stem cells and growth factors.

Stromal Vascular Fraction (SVF) is obtained by lipo-harvesting, procurement, and lipo-transfer as a same day operative procedure to provide therapy to patients with various degenerative and inflammatory diseases. Patients must be 16 years or older, male or female and have a degenerative disease or inflammatory disease that meets criteria for treatment under the IRB which includes: Arthritis, Auto-immune disease, COPD, Cardiomyopathy, Peyronies Disease, Interstitial Cystitis, Erectile Dysfunction, and Neurodegenerative disease such as Parkinson’s, ALS, Neuropathy. Patients must be healthy enough to tolerate a local anesthetic, must not have active cancer or infections.

Dr. Elliot Lander, and Dr. Mark Berman, founders of the Cell Surgical Network Inc. will conduct the study: “Ever since our inception, it’s been our goal to maintain transparency during our investigations. With a closed surgical procedure we can provide effective safety studies and evolve good empirical data that will allow us and others to ultimately refine our protocols,” says Dr. Berman.

The purpose of the safety study is to evaluate for any adverse effects that may be related to the administration and reception of autologous adipose derived stromal vascular fraction (SVF). Secondarily, the study monitors the results of subjective and objective findings as it applies to the non-blinded deployment of autologous SVF for various inflammatory and/or degenerative conditions including select orthopedic, neurologic, urologic and cardio-pulmonary conditions. SVF deployments include intra-venous, intra-articular, and soft tissue injections.

Outcome measures will include the number of participants with adverse events related to either SVF deployment or the lipo-harvesting procedure. Interested patients should contact the treatment center by phone: 800-231-0407 or via email: info(at)cellsurgicalnetwork(dot)com

About Cell Surgical Network:

The affiliates of the Cell Surgical Network (CSN) are devoted to advancing access and quality care in the area of adult stem cell regenerative medicine in order to help people suffering from a variety of inflammatory and degenerative conditions. The Cell Surgical Network was founded nearly two years after the formation of the California Stem Cell Treatment Center (founded in 2010). Affiliate members are generally made up of multi-state and international teams of multidisciplinary physicians in order to best assess and provide care for our patients. The Cell Surgical Network emphasizes quality and is highly committed to clinical research and the advancement of regenerative medicine.

 
Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease.

2017 Jun 16. pii: fj.201700178R. doi: 10.1096/fj.201700178R. [Epub ahead of print]
 
Abstract

Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed the in vivo efficacy of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) on AWR in a murine model of chronic allergic airways disease (AAD)/asthma. Female Balb/c mice were subjected to a 9-wk model of ovalbumin (OVA)-induced chronic AAD and treated intravenously or intranasally with MCA-MSCs from weeks 9 to11. Changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were assessed. OVA-injured mice presented with AI, goblet cell metaplasia, epithelial thickening, increased airway TGF-β1 levels, subepithelial myofibroblast and collagen accumulation, total lung collagen concentration, and AHR (all P < 0.001 vs. uninjured control group). Apart from epithelial thickness, all other parameters measured were significantly, although not totally, decreased by intravenous delivery of MCA-MSCs to OVA-injured mice. In comparison, intranasal delivery of MCA-MSCs to OVA-injured mice significantly decreased all parameters measured (all P < 0.05 vs. OVA group) and, most notably, normalized aberrant airway TGF-β1 levels, airway/lung fibrosis, and AHR to values measured in uninjured animals. MCA-MSCs also increased collagen-degrading gelatinase levels. Hence, direct delivery of MCA-MSCs offers great therapeutic benefit for the AWR and AHR associated with chronic AAD.-Royce, S. G., Rele, S., Broughton, B. R. S., Kelly, K., Samuel, C. S. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease.

KEYWORDS: airway remodeling; asthma; pulmonary delivery; therapies

PMID: 2862602
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Mesenchymal Stem Cell Administration in Patients with Chronic Obstructive Pulmonary Disease: State of the Science.

2017;2017:8916570. doi: 10.1155/2017/8916570. Epub 2017 Feb 20.
 
Abstract

Patients with chronic obstructive pulmonary disease (COPD) have chronic, irreversible airway inflammation; currently, there is no effective or curative treatment and the main goals of COPD management are to mitigate symptoms and improve patients' quality of life. Stem cell based therapy offers a promising therapeutic approach that has shown potential in diverse degenerative lung diseases. Preclinical studies have demonstrated encouraging outcomes of mesenchymal stem/stromal cells (MSCs) therapy for lung disorders including emphysema, bronchopulmonary dysplasia, fibrosis, and acute respiratory distress syndrome. This review summarizes available data on 15 studies currently registered by the ClinicalTrials.gov repository, which used different stem cell therapy protocols for COPD; these included bone marrow mononuclear cells (BMMCs), bone marrow-derived MSCs, adipose-derived stem/stromal cells (ADSCs), and adipose-derived MSCs. Published results of three trials indicate that administering BMMCs or MSCs in the setting of degenerative lung disease is safe and may improve patients' condition and quality of life; however, larger-scale studies are needed to evaluate efficacy. Results of another completed trial (NCT01872624) are not yet published, and eleven other studies are ongoing; these include MSCs therapy in emphysema, several studies of ADSCs in COPD, another in idiopathic pulmonary fibrosis, and plerixafor mobilization of CD117 stem cells to peripheral blood.

PMID: 28303154
 
A protocol proposition of cell therapy for the treatment of chronic obstructive pulmonary disease.

2014 Mar-Apr;20(2):84-91. doi: 10.1016/j.rppneu.2013.06.008. Epub 2013 Nov 26.
 
Abstract

The main feature of pulmonary emphysema is airflow obstruction resulting from the destruction of the alveolar walls distal to the terminal bronchioles. Existing clinical approaches have improved and extended the quality of life of emphysema patients. However, no treatment currently exists that can change the disease course and cure the patient. The different therapeutic approaches that are available aim to increase survival and/or enhance the quality of life of emphysema patients. In this context, cell therapy is a promising therapeutic approach with great potential for degenerative pulmonary diseases. In this protocol proposition, all patients will be submitted to laboratory tests, such as evaluation of heart and lung function and routine examinations. Stem cells will be harvested by means of 10 punctures on each anterior iliac crest, collecting a total volume of 200mL bone marrow. After preparation, separation, counting and labeling (optional) of the mononuclear cells, the patients will receive an intravenous infusion from the pool of Bone Marrow Mononuclear Cells (BMMC). This article proposes a rational and safe clinical cellular therapy protocol which has the potential for developing new projects and can serve as a methodological reference for formulating clinical application protocols related to the use of cellular therapy in COPD. This study protocol was submitted and approved by the Brazilian National Committee of Ethics in Research (CONEP - Brazil) registration number 14764. It is also registered in ClinicalTrials.gov (NCT01110252).

KEYWORDS: Cell therapy; Chronic obstructive pulmonary disease; Células‐tronco; Doença pulmonar obstrutiva crônica; Enfisema pulmonar; Pulmonary emphysema; Stem cells; Terapia celular
PMID: 24287082
 
Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases?

2016 Apr 14;7(1):53. doi: 10.1186/s13287-016-0317-0.
 
Abstract

Extracellular vesicles (EVs) are plasma membrane-bound fragments released from several cell types, including mesenchymal stromal cells (MSCs), constitutively or under stimulation. EVs derived from MSCs and other cell types transfer molecules (such as DNA, proteins/peptides, mRNA, microRNA, and lipids) and/or organelles with reparative and anti-inflammatory properties to recipient cells. The paracrine anti-inflammatory effects promoted by MSC-derived EVs have attracted significant interest in the regenerative medicine field, including for potential use in lung injuries. In the present review, we describe the characteristics, biological activities, and mechanisms of action of MSC-derived EVs. We also review the therapeutic potential of EVs as reported in relevant preclinical models of acute and chronic respiratory diseases, such as pneumonia, acute respiratory distress syndrome, asthma, and pulmonary arterial hypertension. Finally, we discuss possible approaches for potentiating the therapeutic effects of MSC-derived EVs so as to enable use of this therapy in clinical practice.

PMID: 27075363
PMCID: PMC4831172
 
 
Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

2016 Jan 19;17(1). pii: E128. doi: 10.3390/ijms17010128.
 
Abstract

The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.

KEYWORDS: lung development; lung regeneration; lung stem cells; lung tissue engineering; signalling pathways in lung repair; stem cell-mediated therapeutics
PMID: 26797607
 
Specific subsets of mesenchymal stroma cells to treat lung disorders--finding the Holy Grail.
2014 Dec;29(2):93-5. doi: 10.1016/j.pupt.2014.08.001. Epub 2014 Sep 16.
 
Abstract

Accumulating studies, both in animals and human clinical trials with mesenchymal stroma cells (MSC) support the hypothesis of therapeutic effects of these cells in various disorders. However, despite success in immune-mediated disorders such as Crohns' disease, lung disorders such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) treated with MSC have so far not yielded a revolutionary effect on clinical symptoms. Promising data on immunomodulatory effects in COPD have kept nourishing the research into finding specific traits of MSC beneficial in disease. A heterogeneous population of injected cells might drown a potential therapeutic role of a specific group of MSC. Thus careful analysis of MSC regarding their molecular capabilities such as delivering specific therapeutic vesicles to the environment, or plain cytokine/chemokine fingerprinting might prove useful in augmenting therapies against lung diseases.

Copyright © 2014 Elsevier Ltd. All rights reserved.

KEYWORDS: Lung disorders; Mesenchymal stroma cells; Transplantation; Treatment
PMID: 25239767
 
Adipose-Derived Mesenchymal Stem Cells for Treatment of Airway Injuries in A Patient after Long-Term Exposure to Sulfur Mustard.

2017 Apr-Jun;19(1):117-126. Epub 2016 Dec 21.
 
Abstract
OBJECTIVE:

Sulfur mustard (SM) is a potent mutagenic agent that targets several organs, particularly lung tissue. Changes in morphological structure of the airway system are associated with chronic obstructive pulmonary deficiency following exposure to SM. Although numerous studies have demonstrated pathological effects of SM on respiratory organs, unfortunately there is no effective treatment to inhibit further respiratory injuries or induce repair in these patients. Due to the extensive progress and achievements in stem cell therapy, we have aimed to evaluate safety and potential efficacy of systemic mesenchymal stem cell (MSC) administration on a SM-exposed patient with chronic lung injuries.

MATERIALS AND METHODS:

In this clinical trial study, our patient received 100×106cells every 20 days for 4 injections over a 2-month period. After each injection we evaluated the safety, pulmonary function tests (PFT), chronic obstructive pulmonary disease (COPD) Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), Borg Scale Dyspnea Assessment (BSDA), and 6 Minute Walk Test (6MWT). One-way ANOVA test was used in this study which was not significant (P>0.05).

RESULTS:

There were no infusion toxicities or serious adverse events caused by MSC administration. Although there was no significant difference in PFTs, we found a significant improvement for 6MWT, as well as BSDA, SGRQ, and CAT scores after each injection.

CONCLUSION:

Systemic MSC administration appears to be safe in SM-exposed patients with moderate to severe injuries and provides a basis for subsequent cell therapy investigations in other patients with this disorder (Registration Number: IRCT2015110524890N1).

KEYWORDS:

Airway Remodeling; Mesenchymal Stem Cells; Sulfur Mustard; Transplantation

PMID: 28367422
 
Therapeutic Potential of Mesenchymal Stem Cells for the Treatment of Airway Remodeling in Pulmonary Diseases.
Abstract

According to significant improvements in the tissue engineering field over the past several years, lung tissue cells have recently attracted more attention due to the high prevalence and diversity in related diseases. However, selection of an appropriate cell type, screening of suitable conditions for growth and proliferation, as well as subsequent implantation into the body to repair and regenerate damaged tissues are considered as important issues in this context. It should also be noted that most studies have been described in animal models, but not in humans. Because of the high regenerative capacity, predominant immunomodulatory feature, and inhibition of T-lymphocyte proliferation, mesenchymal stem cells (MSCs) may play an important role in the reconstruction of damaged tissues including bronchioles in pulmonary diseases. Interestingly, clinical trial studies demonstrated that MSCs have the significant potential to treat a wide variety of diseases including acute myocardial infarction (AMI), liver cirrhosis, crohn's disease, and graft-versus-host disease (GVHD).

KEYWORDS:

Adipose-derived mesenchymal stem cell; Airway remodeling; Chronic bronchitis; Chronic obstructive pulmonary disease; Inflammation; Lung diseases; Mesenchymal stem cell

PMID: 26725553
 

Immunomodulatory effects of adipose-derived stem cells in airway allergic diseases

Curr Stem Cell Res Ther. 2010 Jun;5(2):111-5.

Cho KS, Roh HJ.

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.

 


Human mesenchymal stem cells resolve airway inflammation, hyperreactivity, and histopathology in a mouse model of occupational asthma.


Stem Cells Dev. 2014 Oct 1;23(19):2352-63. doi: 10.1089/scd.2013.0616. Epub 2014 Jun 19.

Martínez-González I, Cruz MJ, Moreno R, Morell F, Muñoz X, Aran JM.

Abstract
 

Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 × 10(6) cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the AP-injured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA.

 
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