Induction of neural-like differentiation in human mesenchymal stem cells derived from bone marrow, fat, spleen and thymus

Mesenchymal stem cells (MSCs) from bone marrow (BM) and sub-cutaneous fat are known to differentiate into neural cells under appropriate stimuli. We describe here the neural-like differentiation of human MSCs obtained from spleen and thymus, induced either with chemical factors or with co-culture with human Schwann cells (Sc). Under the effect of neural differentiation medium, most MSCs from BM, fat, spleen and thymus acquired morphological changes suggestive of cells of astrocytic/neuronal and oligodendroglial lineages with general up-regulation of neural molecules not correlated with morphological changes. The process was transient and reversible, as MSCs recovered basal morphology and phenotype, as well as their multilineage differentiation potential. Thus, we hypothesized that chemical factors may prime MSCs for neural differentiation, by inducing initial and poorly specific changes. By contrast, co-cultures of MSCs of different origin with Sc induced long-lasting and Sc differentiation, i.e., the expression of Sc myelin proteins for up to 12 days. Our results show that a MSC reservoir is present in tissues other than BM and fat, and that MSCs of different origin have similar neural differentiation potential. This evidence provides new insights into BM-like tissue plasticity and may have important implications for future therapeutic interventions in chronic neuropathies.     

Secondary enuresis and urological manifestations in children with ataxia telangiectasia

Background

Ataxia telangiectasia (AT) is a neurodegenerative cerebellar disorder, caused by mutations in the ATM gene, involved in DNA repair. Radiosensitivity, progressive ataxia, immune deficiency and malignancies, are well known symptoms, but urological manifestations are scarcely described.

Antitumor-promoting activities of hydrolyzable tannins in mouse skin.

Ellagic acid and gallic acid and its derivatives, applied topically to female CF-1 mice 20 min before each 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment inhibit the inductions of epidermal ornithine decarboxylase activity, hydroperoxide production and DNA synthesis caused by this potent tumor promoter in relation with their abilities to inhibit the promotion of skin papillomas and carcinomas in the two-step initiation-promotion protocol. Because of its potency against TPA promotion, tannic acid, which is already known to inhibit tumor initiation, may inhibit the multistage process of carcinogenesis.     

End points in pulmonary arterial hypertension: the way forward.

Pulmonary arterial hypertension is a rare disease of poor prognosis. Despite its rarity >1,000 patients have been randomised in placebo-controlled trials using novel therapies, including prostacyclin analogues, endothelin receptor antagonists and, most recently, phosphodiesterase 5 inhibitors. Nearly all of these trials have used exercise capacity, measured by the unencouraged 6-min walking distance, as the primary end point and a variety of other measurements as secondary end points. This approach has been productive, leading to the licensing of a number of effective treatments. Future clinical trials, however, will probably assess drug combinations, make comparisons between drugs and include less severely ill patients. It is, therefore, timely to examine the end points used. The authors discussed the various end points that have been used in the past and possible end points that might be used in the future. End points considered included measurements of: exercise capacity, haemodynamics, quality of life, imaging of the right heart and circulation, and chemical markers of pulmonary hypertension. Many of these show promise but will have to be used in parallel and compared with conventional end points such as the 6-min walking distance before their value can be demonstrated convincingly to the regulatory authorities.     

alpha1-Adrenoceptors during simulated ischemia and reoxygenation of the human myocardium: effect of the dose and time of administration.

OBJECTIVE: We sought to investigate the effect of alpha1-adrenoceptor activity on the ischemic and reoxygenated human myocardium. METHODS: Right atrial appendages (n = 6 per group) obtained during elective cardiac operations were sliced and stabilized in normoxic normothermic buffer solution for 30 minutes and then subjected to 90 minutes of simulated ischemia, followed by 120 minutes of reoxygenation. In study 1 the dose responses to the alpha1-adrenoceptor agonist phenylephrine (0.01, 0.1, 1, 10, and 100 micromol/L) and to the alpha1-adrenoceptor antagonist prazosin (0.1, 1, 10, and 100 micromol/L) when administered for 10 minutes before ischemia, during ischemia, and during reoxygenation were examined. The influence of the time of administration (ie, before ischemia, during ischemia, or during reoxygenation) of phenylephrine (0.1 micromol/L) and prazosin (10 micromol/L) was then investigated in study 2. In study 3 the effect of the combined administration of phenylephrine given before ischemia and prazosin given during ischemia was investigated. In study 4 the protective effect of phenylephrine given before ischemia (for 10 minutes or for 5 minutes with a 5-minute washout period) was compared with that of ischemic preconditioning (5 minutes of ischemia and 5 minutes of reoxygenation). At the end of each protocol, the leakage of creatine kinase (in units per gram of wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide to insoluble formazan dye (in millimoles per gram of wet weight) were measured. RESULTS: Phenylephrine is maximally beneficial at 0.1 and 1 micromol/L (creatinine kinase, 0.97 +/- 0.06 and 0.95 +/- 0.03 U/g, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 153.0 +/- 7.8 and 156.2 +/- 6.7 mmol/g, respectively) compared with ischemic control (creatine kinase, 1.87 +/- 0.03 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 108.5 +/- 6.8 mmol/g; P <.05) but prazosin is detrimental at concentrations above 10 micromol/L (creatine kinase, 5.22 +/- 0.29 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 69.8 +/- 2.9 mmol/g; P <.05 vs ischemic control). In addition, phenylephrine (0.1 micromol/L) is protective when given before ischemia (creatine kinase, 2.06 +/- 0.21 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 148.5 +/- 4.5 mmol/g; P <.05 vs ischemic control) but is detrimental when given during ischemia alone (creatine kinase, 4.49 +/- 0.98 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 70.5 +/- 6.1 mmol/g; P <.05 vs ischemic control) and has no significant effect during reoxygenation. In contrast, prazosin (10 micromol/L) is beneficial when given during ischemia alone (creatine kinase, 1.34 +/- 0.10 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 148.5 +/- 4.5 mmol/g; P <.05 vs ischemic control), is detrimental when given during reoxygenation alone (creatine kinase, 1.5 +/- 0.16 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 85.0 +/- 4.7 mmol/g; P <.05 vs ischemic control), and has no effect when given before ischemia. The use of phenylephrine before ischemia alone is as protective as prazosin given during ischemia alone, but the combination of the two drugs does not cause additional benefit. Interestingly, the protection afforded by phenylephrine when given before ischemia is similar to that obtained with ischemic preconditioning. CONCLUSIONS: In the human myocardium activation of alpha1-adrenoceptors before ischemia is protective but is detrimental during ischemia, whereas blockade of alpha1-adrenoceptors is beneficial during ischemia but detrimental during reoxygenation. The degree of protection achieved by activation of the alpha1-adrenoceptors before ischemia is similar to that obtained with blockade of alpha1-adrenoceptors during ischemia and that of ischemic preconditioning.