© Springer International Publishing Switzerland 2014
Mieczyslaw Pokorski (ed.)Inflammatory DisordersAdvances in Experimental Medicine and Biology83910.1007/5584_2014_27Stem Cell Experiments Moves into Clinic: New Hope for Children with Bronchopulmonary Dysplasia
(1)
Polish Stem Cell Bank, Warsaw, Poland
(2)
Department of Pediatric Hematology and Oncology, Medical University of Warsaw, 24 Marszałkowska St., 00-576 Warszawa, Poland
(3)
Department of Laboratory Diagnostics and Clinical Immunology, Medical University of Warsaw, Warszawa, Poland
Contributed equally
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease with long-term complications that affects mainly preterm born children with low birth weights, especially those treated with mechanical ventilation and oxygen therapy. Successful treatment of BPD could reduce the incidence of other diseases of prematurity such as periventricular leukomalacia and retinopathy. The effects of current therapies are unsatisfactory; thus, searching for novel therapeutic is underway. One promising approach seems administration of mesenchymal stem cells (MSC). Preclinical data strongly support the role of progenitor cells in the preservation of lung structure. MSC can be found more often in pre-term than term umbilical cord and its isolation from Wharton’s jelly carries a potential in treating diseases of prematurity. Several questions concerning the use of MSC in BPD remain to be answered, including the amount of transferred cells, intervals between infusions, the best route for administration and the timing. MSC can be administered as a treatment or prophylaxis. However, having in mind that not all prematurely born children are at risk of developing bronchopulmonary dysplasia, a search for laboratory markers identifying potential patients should be conducted. This review summarizes the latest achievements in MSC therapy in the context of BPD.
Keywords
Lung diseasesMesenchymal stem cellPrematurityUmbilical cordWharton’s jellyK. Pawelec and D. Gładysz are equally contributors.
1 Introduction
Bronchopulmonary dysplasia (BPD) is a serious lung disorder with long-lasting consequences that develops mainly in preterm children with low birth weights, requiring mechanical ventilation and oxygen therapy. Due to the current achievements in neonatal resuscitation, a growing number of children might be at risk of bronchopulmonary dysplasia. BPD develops in approximately 25 % of infants with birth weight under 1,500 g (Van Marter 2009). In the past, BPD was strongly associated with mechanical injury and oxidative stress, but nowadays its etiology has changed due to noninvasive respiratory support, surfactant therapy, steroid treatment for lung maturity, and advances in neonatal resuscitation. The current pathogenesis is related to immaturity with disordered alveolar and capillary development. The clinical course of the condition has changed as well: cyst-like lesions and intense fibroproliferative changes are now of rare incidence, but impaired alveolar, capillary, and vascular development is more prominent and it is visible as diffuse haziness. A typical clinical setting of BPD have shifted from a near-term infant with gestational age about 32 weeks, birth weight of 1,900 g, and severe airway injury to a preterm neonate of about 24–26 weeks of gestational age, weight of 600 g, and mild airway injury. However, even in milder appearance, the disease still accounts for significant mortality and morbidity among neonates (Bancalari et al. 2003). Bronchopulmonary dysplasia hinders lung function, which can persist into adulthood and puts children at susceptibility of developing chronic obstructive lung disease or early-onset emphysema, with a high probability of neuromotor involvement including cerebral palsy (O’Reilly et al. 2013; Van Marter et al. 2011). Successful treatment of BPD could reduce the incidence of other diseases of prematurity such as periventricular leukomalacia and retinopathy, which share risk factors and pathogenetic mechanisms (Borghesi et al. 2012). The current treatment options for BPD are limited and their results often remain unsatisfactory. Even new promising methods, such as nitric oxide inhalation, are unable to significantly decrease neonatal mortality rate and BPD incidence (Donohue et al. 2011). Therefore, searching for novel therapeutic approaches to treat or even prevent the development of BPD is strongly indicated.
2 Rationale for Using Stem Cells
Recent advances in stem cell research, including pre-clinical experiments on animal models of BPD, provide a strong foundation for moving stem cell therapy into the clinical use. Balasubramaniam et al.’s (2007) study in rodent models gives insight into the BPD pathology and a rationale for using stem cells as therapy. Endothelial progenitor cells (EPC) promote neovascularization and thus contribute to organ repair after vascular injury. Neonatal mice exposed to moderate hyperoxia have lower levels of circulating EPC in the lungs, blood, and bone marrow. However, EPC in adult mice increase while exposed to hyperoxia. To establish the role of progenitor cells, the adult mice were exposed to hyperoxia with subsequent irradiation, and they failed to preserve the lung structure, which implies that functional bone marrow is necessary for the maintenance of pulmonary architecture in an injury model. This results suggest that EPC mobilization plays an important role in adult mice alveolar growth and repair. Borghesi et al. (2009) showed in a group of nearly a hundred preterm infants with gestational age of less than 32 weeks or a birth weight less than 1,500 g that a decrease in endothelial colony-forming cells (ECFC) in the cord blood was connected with increased risk of developing BPD, which could be linked to pulmonary vascular immaturity. A high level of ECFCs seemed to protect infants from developing BPD, even in those with extremely low gestational age. De Paepe et al. (2011) proved that expanded umbilical cord-blood derived hematopoietic stem cells (UCB-HSC) are capable of reconstitution of respiratory epithelium in an animal model of neonatal lung injury acting as a progenitor stem cell of distal respiratory tract. Mao et al. (2013) showed that ex vivo expanded UCB-HSC differentiated into respiratory epithelial cells in the presence of growth factors and cytokines. The expanded cells were applied intranasal to newborn mice with induced lung injury. There was a beneficial effect on lung architecture, but the engraftment rate was very low. Tropea et al. (2012) suggested that positive effects of stem cell therapy could be due to the activation of bronchioalveolar stem cells (the endogenous lung epithelial stem cells) in response to injury, which then contribute to the restoration of pulmonary architecture. The experiment showed increased distribution of bronchioalveolar stem cells in terminal bronchioles after hyperoxia and stem cell therapy, particularly after applying mesenchymal stem cells (MSC)-conditioned media.
3 Mesenchymal Stem Cells
3.1 General Information
Mesenchymal stem cells, according to the criteria formed by the International Society for Cell Therapy (Dominici et al. 2006) are a plastic-adherent population, capable of differentiation into osteoblasts, adipocytes, and chondroblasts under a specific culture condition. These cells have immune-phenotype of CD105+, CD73+, or CD90+ and they lack cell surface antigens of macrophages, monocytes, B-lymphocytes, leukocytes, and MHC class II. Biological characteristic of MSC, their proliferation and differentiation capabilities, the ability to migrate toward injury, and their weakly immunogenic properties, when allo-transplanted, makes them a good candidate for stem cell therapy. The potential of MSC to protect and restore lung structure have already been shown in numerous studies in animal models, and the first clinical trials in humans have been conducted. Zhang et al. (2012) attempted to confirm mesenchymal stem cell capability in treating lung diseases both in vitro and in vivo. Co-culturing of bone marrow-derived stem cell with injured lung tissue enhanced stem cell migration and triggered surfactant protein-C and type II alveolar epithelial cells (AEC2) specific marker expression. Studies in an in vivo mice model of BPD showed no differences between alveolar injury and surfactant protein expression in MSC-treated hyperoxic group and control group. However, MCS were found to improve survival rate, attenuate pulmonary fibrosis by reducing pulmonary expression of genes involved in fibrotic process such as transforming growth factor beta-1 (TGFβ-1), tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen 1α, and to home into injured site more efficiently. Mesenchymal stem cells were applied via intraperitoneal route and they homed into the injured lung and engrafted as AEC2. Oritz et al. (2007) showed that MSC have anti-fibrotic and anti-inflammatory effect through blocking interleukin-1 and tumor necrosis factor-α (TNF-α) in the injured lung.
3.2 Application Routes
The best route of stem cells administration to the neonate with respiratory distress seems to be local. As those children are already given medications intratracheally, this way is most convenient. Chang et al. (2009) examined whether local (intratracheal) or systemic (intraperitoneal) transplantation of human umbilical cord-derived mesenchymal stem cells is more effective in treating BPD in rodents. Hyperoxia-induced impaired alveorization turned out reduced in both groups, but the reduction was prominently smaller in rats that underwent intratracheal transplantation.
3.3 Therapeutic Dose Optimization
Currently, a therapeutic dose of stem cells in humans with BPD is not established. Chang et al. (2011) carried out an animal study aimed at the dose optimization. The rats exposed to hyperoxia were divided into three groups according to the dose of human umbilical cord blood-derived mesenchymal stem cells they received (5 × 103, 5 × 104, or 5 × 105). The hyperoxia-induced pulmonary injury was significantly reduced in those rats which received the medium and highest doses; the effect was more pronounced with the highest MSC dose. Moreover, the presence of donor-derived human RNA in the rodent lungs was dose-depended, with the highest expression in the 5 × 105 MSC group. Also, the inflammatory response and oxidative stress were attenuated in rats receiving the medium and highest doses of MSC. There were no statistical differences in the survival rate between the rats exposed to normoxia, irrespective of the MSC dose.
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