Yingzi Li

Mechanisms of regulating cell topology in proliferating epithelia: impact of division plane, mechanical forces, and cell memory.

Regulation of cell growth and cell division has a fundamental role in tissue formation, organ development, and cancer progression. Remarkable similarities in the topological distributions were found in a variety of proliferating epithelia in both animals and plants. At the same time, there are species with significantly varied frequency of hexagonal cells. Moreover, local topology has been shown to be disturbed on the boundary between proliferating and quiescent cells, where cells have fewer sides than natural proliferating epithelia. The mechanisms of regulating these topological changes remain poorly understood. In this study, we use a mechanical model to examine the effects of orientation of division plane, differential proliferation, and mechanical forces on animal epithelial cells. We find that regardless of orientation of division plane, our model can reproduce the commonly observed topological distributions of cells in natural proliferating animal epithelia with the consideration of cell rearrangements. In addition, with different schemes of division plane, we are able to generate different frequency of hexagonal cells, which is consistent with experimental observations. In proliferating cells interfacing quiescent cells, our results show that differential proliferation alone is insufficient to reproduce the local changes in cell topology. Rather, increased tension on the boundary, in conjunction with differential proliferation, can reproduce the observed topological changes. We conclude that both division plane orientation and mechanical forces play important roles in cell topology in animal proliferating epithelia. Moreover, cell memory is also essential for generating specific topological distributions.

A new realistic geometry spline Laplacian algorithm and its application to VEP

We have developed a new algorithm to estimate the surface Laplacian of the scalp potential on a realistic geometry scalp surface. The performance of the algorithm was evaluated by computer simulations. The algorithm was applied to study the scalp Laplacian maps of visual evoked potentials induced by pattern onset stimuli in a human subject. The present results indicate the excellent performance of the newly developed algorithm and its potential for application in imaging brain electrical activity.

Mechanisms of Regulating Tissue Elongation in Drosophila Wing: Impact of Oriented Cell Divisions, Oriented Mechanical Forces, and Reduced Cell Size

Regulation of cell growth and cell division plays fundamental roles in tissue morphogenesis. However, the mechanisms of regulating tissue elongation through cell growth and cell division are still not well understood. The wing imaginal disc of Drosophila provides a model system that has been widely used to study tissue morphogenesis. Here we use a recently developed two-dimensional cellular model to study the mechanisms of regulating tissue elongation in Drosophila wing. We simulate the effects of directional cues on tissue elongation. We also computationally analyze the role of reduced cell size. Our simulation results indicate that oriented cell divisions, oriented mechanical forces, and reduced cell size can all mediate tissue elongation, but they function differently. We show that oriented cell divisions and oriented mechanical forces act as directional cues during tissue elongation. Between these two directional cues, oriented mechanical forces have a stronger influence than oriented cell divisions. In addition, we raise the novel hypothesis that reduced cell size may significantly promote tissue elongation. We find that reduced cell size alone cannot drive tissue elongation. However, when combined with directional cues, such as oriented cell divisions or oriented mechanical forces, reduced cell size can significantly enhance tissue elongation in Drosophila wing. Furthermore, our simulation results suggest that reduced cell size has a short-term effect on cell topology by decreasing the frequency of hexagonal cells, which is consistent with experimental observations. Our simulation results suggest that cell divisions without cell growth play essential roles in tissue elongation.

Modeling spatial population dynamics of stem cell lineage in tissue growth

Understanding the dynamics of cell population allows insight into the control mechanism of the growth and development of mammalian tissues. It is well known that the proliferation and differentiation among stem cells (SCs), intermediate progenitor cells (IPCs), and fully differentiated cells (FDCs) are under different activation and inhibition controls. Secreted factors in negative feedback loops have already been identified as major elements in regulating the numbers of different cell types and in maintaining the equilibrium of cell populations. We have developed a novel spatial dynamic model of cells. We can characterize not only overall cell population dynamics, but also details of temporal-spatial relationship of individual cells within a tissue. In our model, the shape, growth, and division of each cell are modeled using a realistic geometric model. Furthermore, the inhibited growth rate, proliferation and differentiation probabilities of individual cells are modeled through feedback loops controlled by secreted factors of neighboring cells within a proper diffusion radius. With specific proliferation and differentiation probabilities, the actual division type that each cell will take is chosen by a Monte Carlo sampling process. With simulations we found that with proper strengths of inhibitions to growth and stem cell divisions, the whole tissue is capable of achieving a homeostatic size control. We discuss our findings on control mechanisms of the stability of the tissue development. Our model can be applied to study broad issues on tissue development and pattern formation in stem cell and cancer research.

Mechanical forces mediate localized topological change in epithelia

Regulation of cell growth and proliferation has a fundamental role in tissue development, organogenesis, and disease progression. Conserved distribution of the number of sides of cells with a mean value of six was found in a variety of proliferating epithelia. Previous studies have shown that clones of proliferating cells bounded by quiescent cells have fewer sides than normal epithelia. However, the mechanisms for mediating such localized topological change remain poorly understood. In this study, we use a two-dimensional vertex model with consideration of mechanical forces to investigate how differential proliferation and forces can influence cell shape and tissue morphogenesis, and how they may lead to distorted topological change. We find that differential proliferation alone is insufficient to affect the topology of boundary proliferating cells. Rather, increased surface tension on the boundary, in addition to differential proliferation, can significantly decrease the average number of cell sides. Our results are consistent with experimental observations. We conclude that mechanical forces in addition to localized differential proliferation are required to produce the distorted topological change which significantly impacts the overall cell shape and tissue morphogenesis.

Spontaneous neuronal activity in insula predicts symptom severity of unmedicated obsessive compulsive disorder adults.

Emerging evidence has suggested that the pathophysiology of obsessive compulsive disorder (OCD) might involve widely distributed large-scale brain systems. The dysfunction within salience network, which is comprised of dorsal anterior cingulated cortex (dACC) and bilateral insular areas, has been proposed to contribute to OCD onset. The mechanism underlying salience network abnormality remains unclear and it is worthwhile to investigate its clinical relevance using functional neuroimaging approaches. In this study, we performed the spontaneous brain activity measurement using resting-state functional magnetic resonance imaging (fMRI) on unmedicated OCD patients (n=23). Specifically, the amplitude of low frequency (0.01-0.08 Hz) fluctuations (ALFF) was calculated for regions in salience network. The voxel-based Pearsons correlative analysis was conducted to explore the relationship beween ALFF measures and symptom severity for OCD patients. The results showed that the spontaneous neuronal activity in insula was significantly correlated to OCD clinical symptoms, especially compulsive behaviors. Our findings consolidated that the salience network played an important role in the pathogenesis of OCD and the intensity of intrinsic brain activity in insula provided a predictive biomarker for OCD symptom severity.

White matter integrity correlates with choline level in dorsal anterior cingulate cortex of obsessive compulsive disorder patients: A combined DTI-MRS study

Structural and functional neuroimaging studies have indicated that the cortico-striato -thalamo-cortical (CSTC) circuit contributes to the pathophysiology of obsessive compulsive disorder (OCD). As an essential component of CSTC circuit, the dorsal anterior cingulate cortex (dACC) plays an important role for its advanced function in cognition and emotion control. A comprehensive understanding of the dACC disruption in OCD pathological mechanism is desired. In this study, we performed a combined diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) study in 15 OCD patients and 15 healthy controls to investigate the association between structural abnormality and metabolic alterations within the dACC area. We found a positive correlation between the dACC fractional anisotropy (FA) value and choline concentration in patients. Moreover, the FA was positively associated with OCD clinical symptom, especially the compulsive behavior, which showed the clinical relevance of dACC white matter integrity in OCD. To our knowledge, the present work is the first combined DTI-MRS study of OCD. Our findings demonstrated the co-occurrence of structural and metabolic changes within dACC in OCD patients. It was suggested that the disrupted white matter integrity might be accompanied with degraded cellular membrane turnover.

The cerebral blood flow response dependency on stimulus pulse width is affected by stimulus current amplitude - a study of activation flow coupling.

The coupling of cerebral blood flow (CBF) to neuronal activation, referred to as activation flow coupling (AFC), has been a fundamental brain physiology property. The stimulus-evoked CBF response was usually considered as a surrogate marker for neuronal activity in AFC studies. The selection of appropriate stimulation parameters, e.g., current amplitude and pulse width, is of great importance yet the effect of pulse width changes remained contradictory in previous studies. In this work, we use laser speckle contrast imaging (LSCI) to study the spatiotemporal CBF response to hindpaw somatosensory stimulation of different pulse widths (0.3 ms vs 1 ms) and current amplitudes (3 mA vs 6 mA) in a rodent experiment. The results showed that the change of pulse width significantly affected the CBF peak value at a lower current level (p<;0.05). In addition, the duration for observing significantly different average CBF response, denoted as td, at various pulse widths, was dependent on stimulus current amplitude. At a lower amplitude (3 mA), td was 6.5 s; While at a higher amplitude (6 mA), td was 2.5 s. It was indicated that the changes of pulse width had longer influence on the average CBF response at a lower current amplitude. Our findings may help to understand and explain the inconsistent AFC with different stimulation parameters in fundamental brain physiology.

Effects of mechanical properties on tumor invasion: insights from a cellular model

Understanding the regulating mechanism of tumor invasion is of crucial importance for both fundamental cancer research and clinical applications. Previous in vivo experiments have shown that invasive cancer cells dissociate from the primary tumor and invade into the stroma, forming an irregular invasive morphology. Although cell movements involved in tumor invasion are ultimately driven by mechanical forces of cell-cell interactions and tumor-host interactions, how these mechanical properties affect tumor invasion is still poorly understood. In this study, we use a recently developed two-dimensional cellular model to study the effects of mechanical properties on tumor invasion. We study the effects of cell-cell adhesions as well as the degree of degradation and stiffness of extracellular matrix (ECM). Our simulation results show that cell-cell adhesion relationship must be satisfied for tumor invasion. Increased adhesion to ECM and decreased adhesion among tumor cells result in invasive tumor behaviors. When this invasive behavior occurs, ECM plays an important role for both tumor morphology and the shape of invasive cancer cells. Increased stiffness and stronger degree of degradation of ECM promote tumor invasion, generating more aggressive tumor invasive morphologies. It can also generate irregular shape of invasive cancer cells, protruding towards ECM. The capability of our model suggests it a useful tool to study tumor invasion and might be used to propose optimal treatment in clinical applications.

Early artery blood flow is more prognostic in rodent model of middle cerebral artery occlusion.

Middle cerebral artery occlusion (MCAO) by intraluminal suture is one of the most commonly used stroke models. Our previous study has indicated that the intraoperative cerebral blood flow (CBF) immediately after the stroke is prognostic for long-term permanent injury. The area of more than 50% CBF drop at the first minute after the stroke was found significantly correlated with the lesion size at 24 hours after the stroke. In order to compare the prognostic of different vessels, in this study, we further analyzed the correlation between the CBF levels in major artery, vein and the capillary bed and the lesion volume at 24 hours respectively. The results show that ipsilesional artery blood flow is of more prognostic value in MCAO lesion than the CBF in veins and capillaries.