12 research outputs found
Neuroprotective Effect of Transplanted Human Embryonic Stem Cell-Derived Neural Precursors in an Animal Model of Multiple Sclerosis
BACKGROUND: Multiple sclerosis (MS) is an immune mediated demyelinating disease of the central nervous system (CNS). A potential new therapeutic approach for MS is cell transplantation which may promote remyelination and suppress the inflammatory process. METHODS: We transplanted human embryonic stem cells (hESC)-derived early multipotent neural precursors (NPs) into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of MS. We studied the effect of the transplanted NPs on the functional and pathological manifestations of the disease. RESULTS: Transplanted hESC-derived NPs significantly reduced the clinical signs of EAE. Histological examination showed migration of the transplanted NPs to the host white matter, however, differentiation to mature oligodendrocytes and remyelination were negligible. Time course analysis of the evolution and progression of CNS inflammation and tissue injury showed an attenuation of the inflammatory process in transplanted animals, which was correlated with the reduction of both axonal damage and demyelination. Co-culture experiments showed that hESC-derived NPs inhibited the activation and proliferation of lymph node-derived T cells in response to nonspecific polyclonal stimuli. CONCLUSIONS: The therapeutic effect of transplantation was not related to graft or host remyelination but was mediated by an immunosuppressive neuroprotective mechanism. The attenuation of EAE by hESC-derived NPs, demonstrated here, may serve as the first step towards further developments of hESC for cell therapy in MS
Biophysical Processes in a Urinary Bladder Detrusor Smooth Muscle Cell during Rehabilitation Electrostimulation: a Simulation Study
The work was aimed at the search for approaches to solving the problem of biophysically reasonable
selection of the parameters of electrical stimulation of smooth muscle cells (SMCs) of the urinary
bladder detrusor (UBD). Such stimulation is widely used in the rehabilitation of patients with surgical
correction of congenital malformations accompanied by total or partial deficiency of the M2/M3
cholinergic receptors in the UBD. A computer model built on the basis of experimental data on ion
channels and pumps of the sarcolemma and mechanisms of regulation of the intracellular calcium
concentration ([Ca2+]i), providing both electrogenesis and the contractile function of the cell inherent to
the biological prototype, was used. We studied changes in the membrane potential, partial transmembrane
currents, and [Ca2+]i, caused by depolarizing current pulses applied with constant frequencies and
combined in “packs” or “envelopes” typical of the protocols of rehabilitation stimulation; the stimuli
had constant or trapezoid-modulated amplitudes. The examined UBD SMC responded to a single pulse
by generation of the action potential (AP) close in its properties to the prototype. Stimulation by both
packs and envelopes of identical pulses eventually led to the establishing of equal forced electrical and
concentration oscillations with the parameters depending on the duration of interpulse intervals (IPIs).
Such oscillations caused by stimulation with 5- and 50-msec-long IPIs, typical of the rehabilitation
protocols and comparable with the durations of the absolute and relative refractoriness of the model
SMC, significantly differed in the pattern of the regenerative responses (APs) and in the range and mean
levels of depolarization shifts of the membrane potential and those of [Ca2+]i, which were greater at
high-frequency stimulation. In the case of short IPIs, [Ca2+]i, having no time to return to the basal level,
oscillated within a range of values which in other excitable cells are considered to exceed significantly
the physiological norm. These data emphasize the necessity to estimate the exact kinetic characteristics
of the mechanisms underlying the inflow and extrusion of Ca2+ in the UBD SMC necessary for a
biophysically justified choice of the parameters of rehabilitation stimulation that would prevent possible
cytotoxic side effects associated with excessively long-lasting high levels of [Ca2+]i. Essential for the
observed processes and, therefore, requiring targeted studies, was such a parameter of UBD SMCs as
the reversal potential for Ca2+-dependent chloride current (ECl); this current is activated, in particular,
by parasympathetic action on the M2/M3 receptors. When high-frequency oscillations of the membrane
potential periodically exceeded the ECl level, the mentioned current changed its main (depolarizing)
direction to the opposite (hyperpolarizing) one
Regulation of immune responses by L- arginine metabolism
L-Arginine is an essential amino acid for birds and young mammals, and it is a conditionally essential amino acid for adult mammals, as it is important in situations in which requirements exceed production, such as pregnancy. Recent findings indicate that increased metabolism of L-arginine by myeloid cells can result in the impairment of lymphocyte responses to antigen during immune responses and tumour growth. Two enzymes that compete for L-arginine as a substrate - arginase and nitric-oxide synthase - are crucial components of this lymphocyte-suppression pathway, and the metabolic products of these enzymes are important moderators of T-cell function. This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions