PhD student, Wake Forest Institute of Regenerative Medicine
We are investigating the immunomodulatory properties of perinatal stem cells to treat lung disease
High levels of inflammation are associated with chronic inflammatory and immune mediated conditions such as CF. CF is associated with exaggerated and prolonged inflammation in the lungs, which contributes to lung injury, fibrosis and loss of lung function. When pulmonary infection is apparent in the CF airways, the adaptive and innate immune response is disproportionate and dysregulated. Even in the absence of clinically apparent infection there is often evidence of inflammation in the CF airways. CF patients show elevated levels of neutrophils in the lung, which have increased neutrophil elastase and myeloperoxidase activity. CF macrophages display spontaneous and exaggerated pulmonary infiltration, and are polarized into the M1 pro-inflammatory phenotype and to a lesser extent into the M2 anti-inflammatory phenotype. Cells of the adaptive immune system, such as T lymphocytes are more abundant in CF airways and produce high levels of inflammatory cytokines. Additionally an imbalance of T lymphocyte subsets may have an important role in the CF inflammatory response. Therapeutic regimens for CF generally involve management of symptoms in an attempt to slow the progression of the disease. However, it is the repeated cycles of inflammation, injury and fibrosis that cause the chronic, life-threatening manifestations that ultimately lead to respiratory failure. Thus, therapies that can target this inflammatory environment and disrupt the destructive cycle of infection, inflammation and fibrosis would have a major impact in preventing the progression of lung disease. Perinatal stem cells have anti-inflammatory properties that make them a promising cell therapeutic approach for treating CF.
Hypothesis: We hypothesize that perinatal stem cells are capable of modulating the chronic hyper-inflammatory environment of the CF lung. Results: Perinatal stem cells significantly reduced neutrophil and macrophage pulmonary migration into the lungs of the bleomycin injured mouse, and prevented pulmonary fibrosis and loss of lung function. In human samples, administration of perinatal stem cells decreased of pro-inflammatory cytokines such as IL-6.
These preliminary data suggest that perinatal stem cell therapy may be a useful immune-modulatory therapy for CF.
Abstract: The immunomodulatory and immunosuppressive capacity of human mesenchymal stem cells (hMSC) is well recognized, but efficacies of hMSC in immunocompetent and immunocompromised animals have never been directly compared.We aimed to compare the efficacy of hMSC in preventing bleomycin-induced lung injury in immunocompromised SCID and immunocompetent C57Bl/6 mice.SCID and C57Bl/6 mice were subjected to a single bolus intranasal instillation of bleomycin to induce lung injury. One million hMSC were administered intravenously 24 h following the induction of bleomycin lung injury.hMSC xenotransplantation into SCID mice resulted in transient improvements in lung weight and tidal volume and to persistent improvement in inspiratory duty cycle, inspiratory flow rate and inspiration/expiration ratio. We did not observed protective effects in C57Bl/6 mice. This correlated with histological changes, where hMSC administration reduced Ashcroft scores, collagen deposition and inflammatory influx in the lungs of SCID mice, but not in those of C57Bl/6 mice.The application of hMSC for the treatment of acute and chronic lung injury is significantly affected by the immune status of the recipient. Lack of hMSC-mediated repair observed in C57Bl/6 mice was likely to be due to limitations of their immune privilege and differential priming of hMSC in immunocompetent versus immunocompromised hosts.
Pub.: 05 Dec '12, Pinned: 18 Jul '17
Abstract: Cystic fibrosis, an autosomal recessive disorder caused by a mutation in a gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), remains a leading cause of childhood respiratory morbidity and mortality. The respiratory consequences of cystic fibrosis include the generation of thick, tenacious mucus that impairs lung clearance, predisposing the individual to repeated and persistent infections, progressive lung damage and shortened lifespan. Currently there is no cure for cystic fibrosis. With this in mind, we investigated the ability of human amnion epithelial cells (hAECs) to express functional CFTR. We found that hAECs formed 3-dimensional structures and expressed the CFTR gene and protein after culture in Small Airway Growth Medium (SAGM). We also observed a polarized CFTR distribution on the membrane of hAECs cultured in SAGM, similar to that observed in polarized airway cells in vivo. Further, hAECs induced to express CFTR possessed functional iodide/chloride (I(-/)Cl(-)) ion channels that were inhibited by the CFTR-inhibitor CFTR-172, indicating the presence of functional CFTR ion channels. These data suggest that hAECs may be a promising source for the development of a cellular therapy for cystic fibrosis.
Pub.: 03 Oct '12, Pinned: 18 Jul '17
Abstract: Currently there is no cure for cystic fibrosis (CF). Treatments are focused on addressing the disease symptoms, with varying degrees of success. Regenerative medicine holds the promise of regenerating dysfunctional or damaged tissues and to enhance the body's own endogenous repair mechanisms. The discovery of endogenous and exogenous stem cells has provided valuable tools for development of novel treatments for CF. The ability of stem cells to differentiate into functional pulmonary cells, modulate inflammatory responses and contribute to pulmonary function has provided researchers with multiple approaches to develop effective treatment strategies. Several approaches show promise to produce viable therapeutic treatments to treat the underlying cause of CF, reduce the symptoms and mitigate long-term damage, and generate functional replacement organs for end-stage transplantation. This review provides an overview of the rapidly progressing field of cell therapy for CF, focusing on the various cell types utilized and current strategies that show promise to improve life expectancy and quality of life for CF patients.
Pub.: 31 Jul '13, Pinned: 18 Jul '17
Abstract: Cystic fibrosis (CF) is associated with exaggerated and prolonged inflammation in the lungs, which contributes to lung injury, airway mucus obstruction, bronchiectasis and loss of lung function. This hyper-inflammatory phenotype appears to be caused by an imbalance between the pro- and anti-inflammatory regulatory pathways, with heightened pro-inflammatory stimuli, a decreased counter-regulatory response, and reduced effectiveness of immune cell function and inflammatory resolution. Thus, therapies that can target this inflammatory environment would have a major impact in preventing the progression of lung disease. Due to the complex phenotype of CF inflammation, current anti-inflammatory regimens have proven to be inadequate for the targeting of these multiple dysregulated pathways and effects. Several approaches utilizing cell therapies have shown potential therapeutic benefit for the treatment of CF inflammation. This review provides an overview of the immune dysfunctions in CF and current therapeutic regimens and explores the field of cell therapy as a treatment for CF inflammation, and focuses on the various cell types utilized, their immunomodulatory functions, and the current approaches to mitigate the inflammatory response and reduce the long-term damage for CF patients.
Pub.: 15 Jul '17, Pinned: 18 Jul '17