Leiden University Medical Center, Netherlands. Intravenous Autologous Expanded Bone Marrow Mesenchymal Cells for COPD. Phase I. Currently Recruiting
Laboratório de Genética Humana e Terapia Celular Assis, São Paulo, Brazil.. Safety Study of Cell Therapy to Treat Chronic Obstructive Pulmonary Disease Completed.
This study concluded: “The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease. Therefore, the proposed methodology in this study for BMMC cell therapy in sufferers of advanced COPD was demonstrated to be free of significant adverse effects. Although a larger sample and a greater follow-up period are needed, it is possible to infer that BMMC cell therapy introduces an unprecedented change in the course or in the natural history of emphysema, inhibiting or slowing the progression of disease.” The cells used in the study were from bone marrow. The subjects were pretreated with G-CSF (granulocyte colony-stimulating factor) immediately prior to harvest and then mononuclear cells harvested from bone marrow were given intravenously.
Published study here.
Multi-Center, USA. A Phase II, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of PROCHYMAL™ (ex Vivo Cultured Adult Human Mesenchymal Stem Cells) Intravenous Infusion for the Treatment of Subjects With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)
This study was completed. Inflammation was significantly reduced but lung function endpoints were not met.
Comment: PROCHYMAL™ is comprised of expanded bone marrow mesenchymal stem cells from adult donors. Up to 80 percent of the potentiality of mesenchymal stem cells is depleted between birth and adulthood. It would be interesting to see a trial using donor umbilical cord mesenchymal stem cells. If the same trend occurred as in the Lupus trials of Dr. Sun of Nanjing, China, a better outcome would be expected. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus.
Pulmonary hypertension. Dr. Thébaud and his team used conditioned media from mesenchymal stem cells to treat oxygen-induced lung injury in neonatal rats.
1. Conditioned media from mesenchymal stem cells exposed to 95% oxygen for 24 hours injected IP daily for 21 days prevented pulmonary hypertension.
2. Conditioned media from mesenchymal stem cells exposed to 95% oxygen for 24 hours produced higher levels of the naturally occurring antioxidant stanniocalcin-1 than conditioned media from cells in usual environment.
Stem Cells Dev. 2012 Jun 7. [Epub ahead of print]
Preconditioning Enhances the Paracrine Effect of Mesenchymal Stem Cells in Preventing Oxygen-Induced Neonatal Lung Injury in Rats.
Waszak P, Alphonse R, Vadivel A, Ionescu L, Eaton F, Thébaud B.
Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity. Bone marrow derived-mesenchymal stem cells (BM-MSC) prevent lung injury in an O(2)-induced model of BPD. The low level of lung BM-MSC engraftment suggests alternate mechanisms-beyond cell replacement-to account for their therapeutic benefit. We hypothesized that BM-MSC prevent O(2)-induced BPD through a paracrine-mediated mechanism and that preconditioning of BM-MSC would further enhance this paracrine effect. To this end, conditioned medium (CM) from BM-MSC (MSCcm) or preconditioned CM harvested after 24 h of BM-MSC exposure to 95% O(2) (MSC-O2cm) were administrated for 21 days to newborn rats exposed to 95% O(2) from birth until postnatal day (P)14. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and exhibited signs of pulmonary hypertension (PH), assessed by echo-Doppler, right ventricular hypertrophy, and pulmonary artery medial wall thickness. Daily intraperitoneal administration of both CM preserved alveolar growth. MSC-O2cm exerted the most potent therapeutic benefit and also prevented PH. CM of lung fibroblasts (control cells) had no effect. MSCcm had higher antioxidant capacity than control fibroblast CM. Preconditioning did not increase the antioxidant capacity in MSC-O2cm but produced higher levels of the naturally occurring antioxidant stanniocalcin-1 in MSC-O2cm. Ex vivo preconditioning enhances the paracrine effect of BM-MSC and opens new therapeutic options for cell-based therapies. Ex vivo preconditioning may also facilitate the discovery of MSC-derived repair molecules.
Intravenous mesenchymal stem cells improve rat model of pulmonary hypertension.
Am J Med Sci. 2012 May;343(5):402-6.
Implantation of mesenchymal stem cells improves right ventricular impairments caused by experimental pulmonary hypertension.
Luan Y, Zhang ZH, Wei DE, Zhao JJ, Kong F, Cheng GH, Wang YB.
Pulmonary hypertension (PH) is a rapidly progressive and fatal disease. In recent years, despite drug treatment made significant progress, the prognosis of patients with advanced PH remains extremely poor. The authors implanted bone marrow-derived mesenchymal stem cells (BMSCs) intravenously into the PH model rats and observed the effect of MSCs on right ventricular (RV) impairments.
BMSCs were isolated, cultured from bone marrow of rats and stained with the cross-linkable membrane dye in vitro. One week after, a PH model was induced by subcutaneous injection of monocrotaline, the animals were randomly divided into 4 groups (n = 20 in each group): I, control; II, MSCs implantation; III, PH and IV, PH + MSCs implantation. Two weeks after MSCs implantation, the authors observed the MSC survival and transformation by immunofluorescence microscopy. On the other hand, RV hypertrophy and the elevation of systolic pressure were detected by echocardiography.
Three weeks after monocrotaline injection, RV systolic pressure, mean right ventricular pressure and mean pulmonary arterial pressure were significantly elevated in group III than in group I and II (P < 0.05) but significantly lower in group IV than in group III (P < 0.05). These results showed that implantation of MSCs could improve RV impairments caused by experimental PH. Histochemical results confirmed that transplanted MSCs were still alive after 2 weeks and part of the cells could differentiate into pulmonary vascular endothelial cells. CONCLUSION: Intravenous implantation of MSCs could significantly reduce or even reverse the progression of MCT-induced PH, improve cardiac function and hemodynamics. http://www.ncbi.nlm.nih.gov/pubmed/21876426
Bone Marrow Nucleated Cells, Cultured Bone Marrow Mesenchymal Stem Cells, and Conditioned Media from Cultured Bone Marrow Mesenchymal Stem Cells Repaired Smoking Induced Emphysema
Am J Physiol Lung Cell Mol Physiol. 2011 Sep;301(3):L255-66. Epub 2011 May 27.
Bone marrow cells repair cigarette smoke-induced emphysema in rats.
Huh JW, Kim SY, Lee JH, Lee JS, Van Ta Q, Kim M, Oh YM, Lee YS, Lee SD.
Dept. of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan Univ. School of Medicine, Suwon 440-746, South Korea.
The therapeutic potential of stem cells in chronic obstructive pulmonary disease is not well known although stem cell therapy is effective in models of other pulmonary diseases. We tested the capacities of bone marrow cells (BMCs), mesenchymal stem cells (MSCs), and conditioned media of MSCs (MSC-CM) to repair cigarette smoke-induced emphysema. Inbred female Lewis rats were exposed to cigarette smoke for 6 mo and then received BMCs, MSCs, or MSC-CM from male Lewis rats. For 2 mo after injection, the BMC treatment gradually alleviated the cigarette smoke-induced emphysema and restored the increased mean linear intercept. The BMC treatment significantly increased cell proliferation and the number of small pulmonary vessels, reduced apoptotic cell death, attenuated the mean pulmonary arterial pressure, and inhibited muscularization in small pulmonary vessels. However, only a few male donor cells were detected from 1 day to 1 mo after BMC administration. The MSCs and cell-free MSC-CM also induced the repair of emphysema and increased the number of small pulmonary vessels. Our data show that BMC, MSCs, and MSC-CM treatment repaired cigarette smoke-induced emphysema. The repair activity of these treatments is consistent with a paracrine effect rather than stem cell engraftment because most of the donor cells disappeared and because cell-free MSC-CM also induced the repair.
Umbilical Cord Mesenchymal Stem Cells Have Antifibrotic Effects in Injured Lung
Am J Pathol. 2009 Jul;175(1):303-13. Epub 2009 Jun 4.
Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury.
Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, Boyd R, Trounson A.
Department of Medicine, Monash Immunology and Stem Cell Laboratories, School of Biomedical Sciences, Monash University, Melbourne, Australia. firstname.lastname@example.org
Acute respiratory distress syndrome is characterized by loss of lung tissue as a result of inflammation and fibrosis. Augmenting tissue repair by the use of mesenchymal stem cells may be an important advance in treating this condition. We evaluated the role of term human umbilical cord cells derived from Wharton’s jelly with a phenotype consistent with mesenchymal stem cells (uMSCs) in the treatment of a bleomycin-induced mouse model of lung injury. uMSCs were administered systemically, and lungs were harvested at 7, 14, and 28 days post-bleomycin. Injected uMSCs were located in the lung 2 weeks later only in areas of inflammation and fibrosis but not in healthy lung tissue. The administration of uMSCs reduced inflammation and inhibited the expression of transforming growth factor-beta, interferon-gamma, and the proinflammatory cytokines macrophage migratory inhibitory factor and tumor necrosis factor-alpha. Collagen concentration in the lung was significantly reduced by uMSC treatment, which may have been a consequence of the simultaneous reduction in Smad2 phosphorylation (transforming growth factor-beta activity). uMSCs also increased matrix metalloproteinase-2 levels and reduced their endogenous inhibitors, tissue inhibitors of matrix metalloproteinases, favoring a pro-degradative milieu following collagen deposition. Notably, injected human lung fibroblasts did not influence either collagen or matrix metalloproteinase levels in the lung. The results of this study suggest that uMSCs have antifibrotic properties and may augment lung repair if used to treat acute respiratory distress syndrome.
Intratracheal Mesenchymal Stem Cells Restore Lung Function in Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
Cell Transplant. 2011 Mar 7.
Mesenchymal stem cells restore lung function by recruiting resident and non-resident proteins.
Jungebluth P, Luedde M, Ferrer E, Luedde T, Vucur M, Peinado VI, Go T, Schreiber C, Richthofen MV, Bader A, Haag J, Darsow KH, Bartel SJ, Lange HA, Furlani D, Steinhoff G, Macchiarini P.
Since human lungs are unlikely to repair or regenerate beyond the cellular level, cell therapy has not previously been considered for chronic irreversible obstructive lung diseases. To explore whether cell therapy can restore lung function, we administered allogenic intratracheal mesenchymal stem cell (MSC) in the trachea of rats with chronic thromboembolic pulmonary hypertension (CTEPH), a disease characterized by single or recurrent pulmonary thromboembolic obliteration and progressive pulmonary vascular remodeling. MSCs were retrieved only in high pressure-exposed lungs recruited via a homing stromal derived factor-1 alpha/CXCR4 pathway. After MSC administration, a marked and long-lasting improvement of all clinical parameters and a significant change of the proteome level were detected. Beside a variation of liver proteome, such as Caspase-3, NF- 〈B, Collagen1A1 and 〈-SMA, we also identified more than 300 resident and nonresident lung proteins, e.g. myosin light chain 3 (P16409) or mitochondrial ATP synthase subunit alpha (P15999). These results suggest that cell therapy restores lung function and the therapeutic effects of MSCs may be related to protein-based tissue reconstituting effects.