Autologous bone marrow-derived mononuclear cell therapy in three patients with severe asthma.

BACKGROUND: Despite recent advances in understanding its pathophysiology and development of novel therapies, asthma remains a serious public health issue worldwide. Combination therapy with inhaled corticosteroids and long-acting ß2-adrenoceptor agonists results in disease control for many patients, but those who exhibit severe asthma are often unresponsive to conventional treatment, experiencing worse quality of life, frequent exacerbations, and increasing healthcare costs. Bone marrow-derived mononuclear cell (BMMC) transplantation has been shown to reduce airway inflammation and remodeling and improve lung function in experimental models of allergic asthma. METHODS: This is a case series of three patients who presented severe asthma, unresponsive to conventional therapy and omalizumab. They received a single intravenous dose of autologous BMMCs (2 × 107) and were periodically evaluated for 1 year after the procedure. Endpoint assessments included physical examination, quality of life questionnaires, imaging (computed tomography, single-photon emission computed tomography, and ventilation/perfusion scan), lung function tests, and a 6-min walk test. RESULTS: All patients completed the follow-up protocol. No serious adverse events attributable to BMMC transplantation were observed during or after the procedure. Lung function remained stable throughout. A slight increase in ventilation of the right lung was observed on day 120 after BMMC transplantation in one patient. All three patients reported improvement in quality of life in the early post-procedure course. CONCLUSIONS: This paper described for the first time the effects of BMMC therapy in patients with severe asthma, providing a basis for subsequent trials to assess the efficacy of this therapy.

Reprogramming to a pluripotent state modifies mesenchymal stem cell resistance to oxidative stress.

Properties of induced pluripotent stem cells (iPSC) have been extensively studied since their first derivation in 2006. However, the modification in reactive oxygen species (ROS) production and detoxification caused by reprogramming still needs to be further elucidated. The objective of this study was to compare the response of iPSC generated from menstrual blood-derived mesenchymal stem cells (mb-iPSC), embryonic stem cells (H9) and adult menstrual blood-derived mesenchymal stem cells (mbMSC) to ROS exposure and investigate the effects of reprogramming on cellular oxidative stress (OS). mbMSC were extremely resistant to ROS exposure, however, mb-iPSC were 10-fold less resistant to H(2)O(2), which was very similar to embryonic stem cell sensitivity. Extracellular production of ROS was also similar in mb-iPSC and H9 and almost threefold lower than in mbMSC. Furthermore, intracellular amounts of ROS were higher in mb-iPSC and H9 when compared with mbMSC. As the ability to metabolize ROS is related to antioxidant enzymes, we analysed enzyme activities in these cell types. Catalase and superoxide dismutase activities were reduced in mb-iPSC and H9 when compared with mbMSC. Finally, cell adhesion under OS conditions was impaired in mb-iPSC when compared with mbMSC, albeit similar to H9. Thus, reprogramming leads to profound modifications in extracellular ROS production accompanied by loss of the ability to handle OS.

Effects of mesenchymal stem cell therapy on the time course of pulmonary remodeling depend on the etiology of lung injury in mice.

OBJECTIVE: Recent evidence suggests that mesenchymal stem cells may attenuate lung inflammation and fibrosis in acute lung injury. However, so far, no study has investigated the effects of mesenchymal stem cell therapy on the time course of the structural, mechanical, and remodeling properties in pulmonary or extrapulmonary acute lung injury. DESIGN: Prospective randomized controlled experimental study. SETTING: University research laboratory. SUBJECTS: One hundred forty-three females and 24 male C57BL/6 mice. INTERVENTIONS: Control mice received saline solution intratracheally (0.05 mL, pulmonary control) or intraperitoneally (0.5 mL, extrapulmonary control). Acute lung injury mice received Escherichia coli lipopolysaccharide intratracheally (2 mg/kg in 0.05 mL of saline/mouse, pulmonary acute lung injury) or intraperitoneally (20 mg/kg in 0.5 mL of saline/mouse, extrapulmonary acute lung injury). Mesenchymal stem cells were intravenously injected (IV, 1 × 10 cells in 0.05 mL of saline/mouse) 1 day after lipopolysaccharide administration. MEASUREMENTS AND MAIN RESULTS: At days 1, 2, and 7, static lung elastance and the amount of alveolar collapse were similar in pulmonary and extrapulmonary acute lung injury groups. Inflammation was markedly increased at day 2 in both acute lung injury groups as evidenced by neutrophil infiltration and levels of cytokines in bronchoalveolar lavage fluid and lung tissue. Conversely, collagen deposition was only documented in pulmonary acute lung injury. Mesenchymal stem cell mitigated changes in elastance, alveolar collapse, and inflammation at days 2 and 7. Compared with extrapulmonary acute lung injury, mesenchymal stem cell decreased collagen deposition only in pulmonary acute lung injury. Furthermore, mesenchymal stem cell increased metalloproteinase-8 expression and decreased expression of tissue inhibitor of metalloproteinase-1 in pulmonary acute lung injury, suggesting that mesenchymal stem cells may have an effect on the remodeling process. This change may be related to a shift in macrophage phenotype from M1 (inflammatory and antimicrobial) to M2 (wound repair and inflammation resolution) phenotype. CONCLUSIONS: Mesenchymal stem cell therapy improves lung function through modulation of the inflammatory and remodeling processes. In pulmonary acute lung injury, a reduction in collagen fiber content was observed associated with a balance between metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 expressions.

Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury.

The objective of our study was to evaluate the therapeutic potential of bone marrow mesenchymal stromal cells (MSC) in a rat model of severe chronic liver injury. Fourteen female Wistar rats were fed exclusively an alcoholic liquid diet and received intraperitoneal injections of carbon tetrachloride every other day during 15 weeks. After this period, eight animals (MSC group) had 1 x 10(7) cells injected into the portal vein while six animals (placebo group) received vehicle. Blood analysis was performed to evaluate alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin before cell therapy and 1 and 2 months after cell or placebo infusion. Fibrosis was evaluated before and 1 month after cell or placebo injection by liver biopsies. Two months after cell delivery, animals were sacrificed and histological analysis of the livers was performed. Fibrosis was quantified by histomorphometry. Biopsies obtained before cell infusion showed intense collagen deposition and septa interconnecting regenerative nodules. One month after cell injection, this result was unaltered and differences in fibrosis quantification were not found between MSC and placebo groups. ALT and AST returned to normal values 2 weeks after cell or placebo infusion, without significant differences between experimental groups. Two months after cell or placebo injection, albumin had also returned to normal values and histological results were maintained, again without differences between MSC and placebo groups. Therefore, under our experimental conditions, MSC were unable to reduce fibrosis or improve liver function in a rat model of severe chronic liver injury.