Biomedical subjects

Alexander A Spector

Publications and source records attributed to Alexander A Spector.

12 recordsLinked to original sources

PubMed2005

Effects of chlorpromazine on mechanical properties of the outer hair cell plasma membrane.

An optical tweezers system was used to characterize the effects of chlorpromazine (CPZ) on the mechanical properties of the mammalian outer hair cell (OHC) through the formation of plasma membrane tethers. Such tethers exhibited force relaxation when held at a constant length for several minutes. We used a second-order generalized Kelvin body to model tether-force behavior from which several mechanical parameters were then calculated including stiffness, viscosity-associated measures, and force relaxation time constants. The results of the analysis portray a two-part relaxation process characterized by significantly different rates of force decay, which we propose is due to the local reorganization of lipids within the tether and the flow of external lipid into the tether. We found that CPZ's effect was limited to the latter phenomenon since only the second phase of relaxation was significantly affected by the drug. This finding coupled with an observed large reduction in overall tether forces implies a common basis for the drug's effects, the plasma membrane-cytoskeleton interaction. The CPZ-induced changes in tether viscoelastic behavior suggest that alterations in the mechanical properties of the OHC lateral wall could play a role in the modulation of OHC electromotility by CPZ.

Animals↗

PubMed2005

Emergent patterns of growth controlled by multicellular form and mechanics.

Spatial patterns of cellular growth generate mechanical stresses that help to push, fold, expand, and deform tissues into their specific forms. Genetic factors are thought to specify patterns of growth and other behaviors to drive morphogenesis. Here, we show that tissue form itself can feed back to regulate patterns of proliferation. Using micro-fabrication to control the organization of sheets of cells, we demonstrated the emergence of stable patterns of proliferative foci. Regions of concentrated growth corresponded to regions of high tractional stress generated within the sheet, as predicted by a finite-element model of multicellular mechanics and measured directly by using a micromechanical force sensor array. Inhibiting actomyosin-based tension or cadherin-mediated connections between cells disrupted the spatial pattern of proliferation. These findings demonstrate the existence of patterns of mechanical forces that originate from the contraction of cells, emerge from their multicellular organization, and result in patterns of growth. Thus, tissue form is not only a consequence but also an active regulator of tissue growth.

Animals↗

PubMed2005

High-frequency force generation in the constrained cochlear outer hair cell: a model study.

Cochlear outer hair cell (OHC) electromotility is believed to be responsible for the sensitivity and frequency selectivity of the mammalian hearing process. Its contribution to hearing is better understood by examining the force generated by the OHC as a feedback to vibration of the basilar membrane (BM). In this study, we examine the effects of the constraints imposed on the OHC and of the surrounding fluids on the cell's high-frequency active force generated under in vitro and in vivo conditions. The OHC is modeled as a viscoelastic and piezoelectric cylindrical shell coupled with viscous intracellular and extracellular fluids, and the constraint is represented by a spring with adjustable stiffness. The solution is obtained in the form of a Fourier series. The model results are consistent with previously reported experiments under both low- and high-frequency conditions. We find that constrained OHCs achieve a much higher corner frequency than free OHCs, depending on the stiffness of the constraint. We analyze cases in which the stiffness of the constraint is similar to that of the BM, reticular lamina, and tectorial membrane, and find that the force per unit transmembrane potential generated by the OHC can be constant up to several tens of kHz. This model, describing the OHC as a local amplifier, can be incorporated into a global cochlear model that considers cochlear hydrodynamics and frequency modulation of the receptor potential, as well as the graded BM stiffness and OHC length.

Acoustics↗

PubMed2005

Mechanosensitive channels in the lateral wall can enhance the cochlear outer hair cell frequency response.

We present the results of a modeling study on the impact of mechanosensitive channels in the lateral wall of the outer hair cell on the cell frequency response. The model includes the electrical properties of the cell membrane, piezoelectricity associated with a membrane motor mechanism, and mechanosensitive channels in the cell lateral wall. The outer hair cell is loaded by the vibrating basilar and tectorial membranes, and this loading generates strain in the lateral wall. Our analysis reveals a property, the strain rate sensitivity, that, in concert with the piezoelectric effect, can enhance the cell frequency response. We discuss possible viscoelastic-type mechanisms of the channel's strain rate sensitivity that is consistent with the organization of the composite cell lateral wall. The parameters of our model are chosen on the basis of the previously estimated electrical and piezoelectric properties as well as typical conductance and density of the mechanosensitive channels in cells. We found that the strain rate sensitivity of the channels can result in receptor potentials greater than those predicted by the RC (resistance and capacitance) analysis. The effect of the channels is especially significant in an intermediate range of sound frequencies, and the channel-related gain is up to 3-4 times between 3 and 15 kHz.

Acoustics↗

PubMed2005

Effectiveness, active energy produced by molecular motors, and nonlinear capacitance of the cochlear outer hair cell.

Cochlear outer hair cells are crucial for active hearing. These cells have a unique form of motility, named electromotility, whose main features are the cell's length changes, active force production, and nonlinear capacitance. The molecular motor, prestin, that drives outer hair cell electromotility has recently been identified. We reveal relationships between the active energy produced by the outer hair cell molecular motors, motor effectiveness, and the capacitive properties of the cell membrane. We quantitatively characterize these relationships by introducing three characteristics: effective capacitance, zero-strain capacitance, and zero-resultant capacitance. We show that zero-strain capacitance is smaller than zero-resultant capacitance, and that the effective capacitance is between the two. It was also found that the differences between the introduced capacitive characteristics can be expressed in terms of the active energy produced by the cell's molecular motors. The effectiveness of the cell and its molecular motors is introduced as the ratio of the motors'active energy to the energy of the externally applied electric field. It is shown that the effectiveness is proportional to the difference between zero-strain and zero-resultant capacitance. We analyze the cell and motor's effectiveness within a broad range of cellular parameters and estimate it to be within a range of 12%-30%.

Animals↗

PubMed2005

Finite-element analysis of the adhesion-cytoskeleton-nucleus mechanotransduction pathway during endothelial cell rounding: axisymmetric model.

Endothelial cells possess a mechanical network connecting adhesions on the basal surface, the cytoskeleton, and the nucleus. Transmission of force at adhesions via this pathway can deform the nucleus, ultimately resulting in an alteration of gene expression and other cellular changes (mechanotransduction). Previously, we measured cell adhesion area and apparent nuclear stretch during endothelial cell rounding. Here, we reconstruct the stress map of the nucleus from the observed strains using finite-element modeling. To simulate the disruption of adhesions, we prescribe displacement boundary conditions at the basal surface of the axisymmetric model cell. We consider different scenarios of the cytoskeletal arrangement, and represent the cytoskeleton as either discrete fibers or as an effective homogeneous layer When the nucleus is in the initial (spread) state, cytoskeletal tension holds the nucleus in an elongated, ellipsoidal configuration. Loss of cytoskeletal tension during cell rounding is represented by reactive forces acting on the nucleus in the model. In our simulations of cell rounding, we found that, for both representations of the cytoskeleton, the loss of cytoskeletal tension contributed more to the observed nuclear deformation than passive properties. Since the simulations make no assumption about the heterogeneity of the nucleus, the stress components both within and on the surface of the nucleus were calculated. The nuclear stress map showed that the nucleus experiences stress on the order of magnitude that can be significant for the function of DNA molecules and chromatin fibers. This study of endothelial cell mechanobiology suggests the possibility that mechanotransduction could result, in part, from nuclear deformation, and may be relevant to angiogenesis, wound healing, and endothelial barrier dysfunction.

Animals↗

PubMed2005

Modeling high-frequency electromotility of cochlear outer hair cell in microchamber experiment.

Cochlear outer hair cells (OHC) are critically important for the amplification and sharp frequency selectivity of the mammalian ear. The microchamber experiment has been an effective tool to analyze the OHC high-frequency performance. In this study, the OHC electrical stimulation in the microchamber is simulated. The model takes into account the inertial and viscous properties of fluids inside and outside the cell as well as the viscoelastic and piezoelectric properties of the cell composite membrane (wall). The closed ends of the cylindrical cell were considered as oscillatory rigid plates. The final solution was obtained in terms of Fourier series, and it was checked against the available results of the microchamber experiment. The conditions of the interaction between the cell and pipette was analyzed, and it was found that the amount of slip along the contact surface has a significant effect on the cell electromotile response. The cell's length changes were computed as a function of frequency, and their dependence on the viscosities of both fluids and the cell wall was analyzed. The distribution of the viscous losses inside the fluids was also estimated. The proposed approach can help in a better understanding of the high-frequency OHC electromotility under experimental and physiological conditions.

Cell Movement↗

PubMed2005

Effect of voltage-dependent membrane properties on active force generation in cochlear outer hair cell.

A computational model is proposed to analyze the active force production in an individual outer hair cell (OHC) under high-frequency conditions. The model takes into account important biophysical properties of the cell as well as constraints imposed by the surrounding environment. The biophysical properties include the elastic, piezoelectric, and viscous characteristics of the cell wall. The effect of the environment is associated with the stiffness of the constraint and the drag forces acting on the cell due to the interaction with the external and internal viscous fluids. The study concentrated on a combined effect of the transmembrane potential, frequency, and stiffness of the constraints. The effect of the voltage-dependent stiffness of the cell was particularly investigated and it was found to be twofold. First, it results in higher sensitivity and nonlinearity of the OHC active force production in the physiological range. Second, it determines smaller active forces in the hyperpolarization range. The resonant properties of the active force as functions of voltage and the constraint stiffness were also analyzed. The obtained results can be important for a better understanding of the OHC active force production and the contribution of cell electromotility to the cochlear amplification, sensitivity, and nonlinearity.

Acoustics↗

PubMed2004

Modes and balance of energy in the piezoelectric cochlear outer hair cell wall.

Here, we analyze energy transformations in the outer hair cell and its effectiveness as a piezoelectric-type actuator in the cochlea. The major modes of energy are introduced, and a method to estimate the coefficients of their tension-dependence is proposed. Next, we derive balance of the mechanical and electrical parts of energy, and show two forms of the active energy associated with the motors driving electromotility. The two forms of the active energy, stored mechanical energy, and external electrical work are then introduced as functions of voltage and applied force. We use the energy balance to introduce and estimate the effectiveness of the cell's electromotile response.

Animals↗

PubMed2004

Characterization of the nuclear deformation caused by changes in endothelial cell shape.

We investigated the mechanotransduction pathway in endothelial cells between their nucleus and adhesions to the extracellular matrix. First, we measured nuclear deformations in response to alterations of cell shape as cells detach from a flat surface. We found that the nuclear deformation appeared to be in direct and immediate response to alterations of the cell adhesion area. The nucleus was then treated as a neo-Hookean compressible material, and we estimated the stress associated with the cytoskeleton and acting on the nucleus during cell rounding. With the obtained stress field, we estimated the magnitude of the forces deforming the nucleus. Considering the initial and final components of this adhesion-cytoskeleton-nucleus force transmission pathway, we found our estimate for the internal forces acting on the nucleus to be on the same order of magnitude as previously measured traction forces, suggesting a direct mechanical link between adhesions and the nucleus.

Animals↗

PubMed2003

Effect of outer hair cell piezoelectricity on high-frequency receptor potentials.

The low-pass voltage response of outer hair cells predicted by conventional equivalent circuit analysis would preclude the active force production at high frequencies. We have found that the band pass characteristics can be improved by introducing the piezoelectric properties of the cell wall. In contrast to the conventional analysis, the receptor potential does not tend to zero and at any frequency is greater than a limiting value. In addition, the phase shift between the transduction current and receptor potential tends to zero. The piezoelectric properties cause an additional, strain-dependent, displacement current in the cell wall. The wall strain is estimated on the basis of a model of the cell deformation in the organ of Corti. The limiting value of the receptor potential depends on the ratio of a parameter determined by the piezoelectric coefficients and the strain to the membrane capacitance. In short cells, we have found that for the low-frequency value of about 2-3 mV and the strain level of 0.1% the receptor potential can reach 0.4 mV throughout the whole frequency range. In long cells, we have found that the effect of the piezoelectric properties is much weaker. These results are consistent with major features of the cochlear amplifier.

Cell Size↗

PubMed2002

Nanostructure, effective properties, and deformation pattern of the cochlear outer hair cell cytoskeleton.

We consider the mechanical properties of the outer hair cell cytoskeleton. The cytoskeleton is represented as a set of microdomains of different sizes and orientations composed of actin filaments and spectrin crosslinks. An intermediate material between domains is also introduced. The domain characteristics are randomly generated and the histograms of the cytoskeleton stiffness moduli are obtained. We solve an inverse problem and estimate the stiffness of the crosslink and connective molecule in the intermediate material. We discovered a pattern of highly inhomogeneous deformation of the cytoskeleton where the circumferential strain is primarily determined by the deformation of the intermediate material.

Animals↗