Mesenchymal stem cells regulate airway contractile tissue remodeling in murine experimental asthma.

BACKGROUND: Mesenchymal stem cells may offer therapeutic potential for asthma due to their immunomodulatory properties and host tolerability, yet prior evidence suggests that bloodborne progenitor cells may participate in airway remodeling. Here, we tested whether mesenchymal stem cells administered as anti-inflammatory therapy may favor airway remodeling and therefore be detrimental. METHODS: Adipose tissue-derived mesenchymal stem cells were retrovirally transduced to express green fluorescent protein and intravenously injected into mice with established experimental asthma induced by repeat intranasal house dust mite extract. Controls were house dust mite-instilled animals receiving intravenous vehicle or phosphate-buffered saline-instilled animals receiving mesenchymal stem cells. Data on lung function, airway inflammation, and remodeling were collected at 72 h after injection or after 2 weeks of additional intranasal challenge. RESULTS: The mesenchymal stem cells homed to the lungs and rapidly downregulated airway inflammation in association with raised T-helper-1 lung cytokines, but such effect declined under sustained allergen challenge despite a persistent presence of mesenchymal stem cells. Conversely, airway hyperresponsiveness and contractile tissue underwent a late reduction regardless of continuous pathogenic stimuli and inflammatory rebound. Tracking of green fluorescent protein did not show mesenchymal stem cell integration or differentiation in airway wall tissues. CONCLUSIONS: Therapeutic mesenchymal stem cell infusion in murine experimental asthma is free of unwanted pro-remodeling effects and ameliorates airway hyper-responsiveness and contractile tissue remodeling. These outcomes support furthering the development of mesenchymal stem cell-based asthma therapies, although caution and solid preclinical data building are warranted.

Mobilisation of mesenchymal cells in cardiac patients: is intense exercise necessary?

Circulating mesenchymal cells (cMCs) have a potential for regenerating damaged tissue, e.g., ischaemic myocardium. In patients (age range: 53-76 years) with stable coronary artery disease cMCs were determined before and after dynamic exercise of moderate (< respiratory compensation threshold (RCT)) (n = 9 patients) or high intensity (>RCT) (n = 11). Only high-intensity exercise (i.e., provoking signs of myocardial ischaemia in 3 patients and ventricular extrasystoles in another) induced a significant increase in cMCs (p = 0.009). These results support the hypothesis that intense exercise (near or at the point of myocardial ischaemia) is a potent stimulus for MC mobilisation.

Human Menstrual Blood-Derived Mesenchymal Stem Cells as Potential Cell Carriers for Oncolytic Adenovirus.

Antitumor efficacy of systemically administered oncolytic adenoviruses (OAdv) is limited due to diverse factors such as liver sequestration, neutralizing interactions in blood, elimination by the immune system, and physical barriers in tumors. It is therefore of clinical relevance to improve OAdv bioavailability and tumor delivery. Among the variety of tumor-targeting strategies, the use of stem cells and specifically bone marrow-derived mesenchymal stem cells (BM-MSCs) is of particular interest due to their tumor tropism and immunomodulatory properties. Nonetheless, the invasive methods to obtain these cells, the low number of MSCs present in the bone marrow, and their restricted in vitro expansion represent major obstacles for their use in cancer treatments, pointing out the necessity to identify an alternative source of MSCs. Here, we have evaluated the use of menstrual blood-derived mesenchymal stem cells (MenSCs) as cell carriers for regional delivery of an OAdv in the tumor. Our results indicate that MenSCs can be isolated without invasive methods, they have an increased proliferation rate compared to BM-MSCs, and they can be efficiently infected with different serotype 5-based capsid-modified adenoviruses, leading to viral replication and release. In addition, our in vivo studies confirmed the tumor-homing properties of MenSCs after regional administration.

Mobilisation of mesenchymal cells into blood in response to skeletal muscle injury.

Mesenchymal cells recruited to damaged tissues must circulate through the bloodstream. The absolute numbers of circulating mesenchymal stem cells (cMSCs) in two different models of acute and chronic skeletal muscle injury were determined. cMSCs were present in significantly higher numbers in both models than in healthy controls. These results support the hypothesis that MSCs are mobilised into the bloodstream after skeletal muscle tissue damage. These two models (acute and chronic) would be of value in the search for molecular mediators of mobilisation of MSCs into the circulation.

[Twenty years of treating childhood acute lymphoblastic leukemia]. / Veinte años de experiencia en el tratamiento de la leucemia linfoblástica aguda.

BACKGROUND: Conventional prognostic factors for relapse in patients with acute lymphoblastic leukemia (ALL) are the main basis of risk-stratified treatments. OBJECTIVES: To analyze conventional risk factors for relapse and design a predictive model for relapse in our series, after 20 years of experience in treating ALL. PATIENTS AND METHOD: We performed a multivariate analysis of conventional prognostic factors in the treatment of ALL in our unit and compared them with the risk groups in the Berlin-Frankfurt-Münster (BFM-ALL) treatment protocols. RESULTS: Between 1984 and 2004, 232 children were diagnosed with ALL and treated according to the different versions of the BFM protocols (BFM83, BFM86, BFM90 and BFM95) at the Hospital Niño Jesús, Madrid, Spain. The event-free survival for all patients was 79.4 % (95 % CI: 72.7-85.4). Overall survival among patients who relapsed was 10.72 % (95 % CI: 6-27.3). The only significant prognostic factor for relapse identified by multivariate analysis was leukocyte [white blood cell (WBC)] count higher than 80,000/ml at diagnosis (hazard ratio [HR]: 4.63; 95 % CI: 1.61-13.3; p 5 0,004). The sensitivity and specificity of WBC in predicting relapses were 31.4 % and 87.5 %, respectively. The sensitivity and specificity of BFM risk group stratification in predicting relapses were 25 and 85.9 respectively. CONCLUSIONS: A leukocyte count at diagnosis higher than 80,000/ml and BFM risk-stratified treatment have insufficient sensitivity and specificity to identify relapses.

Transplantation of syngenic bone marrow contaminated with NGFr-marked WEHI-3B cells: an improved model of leukemia relapse in mice.

With the aim of developing a model mimicking the relapse of patients transplanted with leukemia-contaminated grafts, myelomonocytic leukemia WEHI-3B D+ cells were first transduced with a retroviral vector encoding the low-affinity human nerve growth factor receptor (NGFr). Clones with a stable and homogeneous expression of the transgene and with a similar in vitro behavior to the parental cell line were selected for further experiments. The analysis of bone marrow (BM) contaminated with WEHI-3B/NGFr cells revealed a linear correlation (r2 = 0.999) between the actual values of BM contamination and the experimental data determined by flow cytometry. Balb/c mice were myeloablated and transplanted with syngenic BM contaminated with graded numbers of leukemic cells; dose-dependent survival curves were obtained, regardless of whether parental or WEHI-3B/NGFr cells were infused. The leukemia dissemination in recipients transplanted with WEHI-3B/NGFr contaminated grafts was easily determined by means of simple flow cytometry analysis of the NGFr marker. A leukemia dose-dependent increase in the number of PB leukocytes was observed in transplanted recipients at 20 days post-transplantation with no changes in myelomonocytic cells. As deduced from our observations, the transplantation of syngenic BM contaminated with WEHI-3B/NGFr cells constitutes an improved model of autograft-mediated leukemia relapse and a good tool for studies of leukemia cell purging.

Nictitating membrane in trisomy 18 syndrome.

A 2,290-g infant boy born after a 43-week gestation had the classic, somatic, and dermatoglyphic findings of trisomy 18 (Edwards) syndrome. The diagnosis was established cytogenetically. A bilateral nictitating membrane was present. In contrast to those in lower species this membrane was established horizontally and moved cephalad for closure. Thus, the membrane occasionally coverd the conjunctiva and cornea completely, giving the impression of corneal clouding. Postmortem studies were not permitted.

Diabetes and osteoporosis: Action of gastrointestinal hormones on the bone. / Diabetes y osteoporosis: acción de las hormonas gastrointestinales sobre el hueso.

A 62-year-old woman consulted for evaluation of treatment for her type 2 diabetes diagnosed four years ago. He had been received treatment with metformin 850mg twice, with no chronic associated complications. She had hypertension and dyslipidemia. She was being treated with candesartan/hydrochlorothiazide 32/12.5mg and atorvastatin 40mg. Her weight was 92kg and height 162cm (BMI, 35.1kg/m(2)). The last analysis showed fasting glucose 168mg/dl and glycated hemoglobin 7.5%, Microalbuminuria was negative. Blood pressure and lipid profile were within the therapeutic range. Two years ago she suffered a nontraumatic Colle's fracture in her left arm for which she was taking a daily calcium and vitamin D supplement and weekly alendronate. In summary, this is an obese female patient with type 2 diabetes mellitus and inadequate metabolic control, She also has a history of fragility fracture. How should this patient be evaluated and treated?

Generación de células mesenquimales con potencial osteogénico mejorado genéticamente para el tratamiento de enfermedades que cursan con defectos de masa ósea / Generation of human mesenchymal cells with genetically improved osteogenic potential for treatment of bone diseases

Objetivo: Generar células madre mesenquimales humanas (MSCs) modificadas para optimizar su potencial de diferenciación osteogénica, destinadas a su empleo en implantes cerámicos para regeneración ósea. Material y método: Se emplearon ratones inmunodeficientes NOD/SCID (3-6 ratones por condición experimental y ensayo) y se generaron vectores lentivirales basados en la recombinasa Cre, que sobreexpresan el factor regulador del proceso osteogénico Dlx5 (o la proteína fluorescente GFP como control) de forma autolimitada en el tiempo. Estos vectores se utilizaron para transducir hMSCs, y su potencial osteogénico se analizó in vitro e in vivo en un modelo de formación de hueso heterotópico en ratón. Resultados: Las hMSCs transducidas con los vectores que expresan Dlx5 de forma autolimitada fueron capaces de diferenciarse eficientemente a hueso de forma espontánea, de manera similar a las hMSCs control en presencia del factor osteoinductor BMP-2. Conclusión: Hemos desarrollado un sistema de modificación de hMSCs para aumentar su potencial osteogénico que consiste en un vector lentiviral que expresa el factor osteoinductor Dlx5 de forma autolimitada. Las hMSCs modificadas diferencian a hueso de manera eficiente, tanto in vitro como in vivo (AU)

Objective: This article proposes the generation of modified human mesenchymal stem cells (hMSCs) for optimizing their osteogenic differentiation potential, in order to be employed in ceramic implants for bone regeneration. Material and method: We have generated lentiviral vectors based on Cre recombinase, which lead to overexpression of a regulatory factor of osteogenic process, Dlx5 (or GFP fluorescent protein as a control), in a selflimited fashion. We have transduced hMSCs with these vectors, and we have analyzed their osteogenic potential both in vitro and in vivo in a model of heterotopic bone formation in mice. For this purpose we have used immunodeficient NOD/SCID mice (3-6 mice per condition and experiment). Results: hMSCs transduced with self-limited Dlx5-expressing vectors efficiently differentiate into bone in vitro and in vivo, similar to control hMSCs in the presence of osteoinductive factor BMP-2. Conclusion: We have developed a system to modify hMSCs in order to improve their osteogenic potential. This system consists of a lentiviral vector which expresses osteoinductive factor Dlx5 in a self-limited fashion. Modified hMSCs efficiently differentiate into bone, both in vitro and in vivo (AU)

Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study.

Treatment of metastatic tumors with engineered adenoviruses that replicate selectively in tumor cells is a new therapeutic approach in cancer. Systemic administration of these oncolytic adenoviruses lack metastatic targeting ability. The tumor stroma engrafting property of intravenously injected mesenchymal stem cells (MSCs) may allow the use of MSCs as cellular vehicles for targeted delivery. In this work, we study the safety and the efficacy of infusing autologous MSCs infected with ICOVIR-5, a new oncolytic adenovirus, for treating metastatic neuroblastoma. Four children with metastatic neuroblastoma refractory to front-line therapies received several doses of autologous MSCs carrying ICOVIR-5, under an approved preliminary study. The tolerance to the treatment was excellent. A complete clinical response was documented in one case, and the child is in complete remission 3 years after this therapy. We postulate that MSCs can deliver oncolytic adenoviruses to metastatic tumors with very low systemic toxicity and with beneficial antitumor effects.

Mesenchymal stem cells and their use as cell replacement therapy and disease modelling tool.

Mesenchymal stem cells (MSCs) from adult somatic tissues may differentiate in vitro and in vivo into multiple mesodermal tissues including bone, cartilage, adipose tissue, tendon, ligament or even muscle. MSCs preferentially home to damaged tissues where they exert their therapeutic potential. A striking feature of the MSCs is their low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes and antigen-presenting cells. Instead, MSCs appear to be immunosuppressive in vitro. Their multilineage differentiation potential coupled to their immuno-privileged properties is being exploited worldwide for both autologous and allogeneic cell replacement strategies. Here, we introduce the readers to the biology of MSCs and the mechanisms underlying immune tolerance. We then outline potential cell replacement strategies and clinical applications based on the MSCs immunological properties. Ongoing clinical trials for graft-versus-host-disease, haematopoietic recovery after co-transplantation of MSCs along with haematopoietic stem cells and tissue repair are discussed. Finally, we review the emerging area based on the use of MSCs as a target cell subset for either spontaneous or induced neoplastic transformation and, for modelling non-haematological mesenchymal cancers such as sarcomas.