The CADUCEUS trial of cardiosphere-derived cells (CDCs) has shown that it may be possible to regenerate injured heart muscle previously thought to be permanently scarred. The mechanisms of benefit are known to be indirect, but the mediators have yet to be identified. Here we pinpoint exosomes secreted by human CDCs as critical agents of regeneration and cardioprotection. CDC exosomes inhibit apoptosis and promote proliferation of cardiomyocytes, while enhancing angiogenesis. Injection of exosomes into injured mouse hearts recapitulates the regenerative and functional effects produced by CDC transplantation, whereas inhibition of exosome production by CDCs blocks those benefits. CDC exosomes contain a distinctive complement of microRNAs, with particular enrichment of miR-146a. Selective administration of a miR-146a mimic reproduces some (but not all) of the benefits of CDC exosomes. The findings identify exosomes as key mediators of CDC-induced regeneration, while highlighting the potential utility of exosomes as cell-free therapeutic candidates.

https://www.cell.com/stem-cell-reports/pdf/S2213-6711%2814%2900113-1.pdf

Exosomes as critical agents of cardiac regeneration triggered by cell therapy.

Despite major scientific, medical and technological advances over the last few decades, a cure for cancer remains elusive. The disease initiation is complex, and including initiation and avascular growth, onset of hypoxia and acidosis due to accumulation of cells beyond normal physiological conditions, inducement of angiogenesis from the surrounding vasculature, tumour vascularization and further growth, and invasion of surrounding tissue and metastasis. Although the focus historically has been to study these events through experimental and clinical observations, mathematical modelling and simulation that enable analysis at multiple time and spatial scales have also complemented these efforts. Here, we provide an overview of this multiscale modelling focusing on the growth phase of tumours and bypassing the initial stage of tumourigenesis. While we briefly review discrete modelling, our focus is on the continuum approach. We limit the scope further by considering models of tumour progression that do not distinguish tumour cells by their age. We also do not consider immune system interactions nor do we describe models of therapy. We do discuss hybrid-modelling frameworks, where the tumour tissue is modelled using both discrete (cell-scale) and continuum (tumour-scale) elements, thus connecting the micrometre to the centimetre tumour scale. We review recent examples that incorporate experimental data into model parameters. We show that recent mathematical modelling predicts that transport limitations of cell nutrients, oxygen and growth factors may result in cell death that leads to morphological instability, providing a mechanism for invasion via tumour fingering and fragmentation. These conditions induce selection pressure for cell survivability, and may lead to additional genetic mutations. Mathematical modelling further shows that parameters that control the tumour mass shape also control its ability to invade. Thus, tumour morphology may serve as a predictor of invasiveness and treatment prognosis.

https://iopscience.iop.org/article/10.1088/0951-7715/23/1/R01/pdf

Nonlinear modelling of cancer: Bridging the gap between cells and tumours

3 Early Events in Angiogenesis 6 3.1 Signaling From Tumor To Vessel at the Onset of Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1.1 Transforming Growth Factor Beta (TGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3.1.2 Basic Fibroblast Growth Factor (bFGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.1.3 Vascular Endothelial Growth Factor (VEGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.2 Modifications of the ECM that Facilitate EC Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.2.1 The PA-Plasmin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3.2.2 The MMP Family of Proteinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

/pdf/mathematical-modeling-of-tumor-induced-angiogenesis-2d8a0lje6y.pdf

Mathematical modeling of tumor-induced angiogenesis

The continuum mechanical treatment of biological growth and remodeling has attracted considerable attention over the past fifteen years Many aspects of these problems are now well-understood, yet there remain areas in need of significant development from the standpoint of experiments, theory, and computation In this perspective paper we review the state of the field and highlight open questions, challenges, and avenues for further development

Perspectives on biological growth and remodeling

In vitro models of vasculogenesis and angiogenesis.

Endothelial cells, when cultured on gelled basement membrane matrix exert forces of tension through which they deform the matrix and at the same time they aggregate into clusters. The cells eventually form a network of cord-like structures connecting cell aggregates. In this network, almost all of the matrix has been pulled underneath the cell cords and cell clusters. This phenomenon has been proposed as a possible model for the growth and development of planar vascular systems in vitro. Our hypothesis is that the matrix is reorganized and the cellular networks form as a result of traction forces exerted by the cells on the matrix and the latter's elasticity. We construct and analyze a mathematical model based on this hypothesis and examine conditions necessary for the formation of the pattern. We show cell migration is not necessary for pattern formation and that isotropic, strain-stimulated traction is sufficient to form the observed patterns.

A mechanical model for the formation of vascular networks in vitro.

The conventional theory about the snail shell shape of the mammalian cochlea is that it evolved essentially and perhaps solely to conserve space inside the skull. Recently, a theory proposed that the spiral's graded curvature enhances the cochlea's mechanical response to low frequencies. This article provides a multispecies analysis of cochlear shape to test this theory and demonstrates that the ratio of the radii of curvature from the outermost and innermost turns of the cochlear spiral is a significant cochlear feature that correlates strongly with low-frequency hearing limits. The ratio, which is a measure of curvature gradient, is a reflection of the ability of cochlear curvature to focus acoustic energy at the outer wall of the cochlear canal as the wave propagates toward the apex of the cochlea.

https://www.pnas.org/content/pnas/105/16/6162.full.pdf

The influence of cochlear shape on low-frequency hearing

In the ear, sound processing takes place on the cochlea’s basilar membrane (BM). Sounds are transmitted to the cochlear fluids, which interact mechanically with the membrane, causing it to vibrate in the form of a traveling wave that propagates along the membrane’s length (Fig. 1). Because of the BM’s graded stiffness, wave amplitude changes as the wave propagates and is maximized at a membrane stiffness characteristic to a certain frequency. The BM thus decomposes incoming sounds into their component frequencies, and is often characterized as a Fourier analyzer designed by nature. Other anatomical features of the cochlea have also been shown to affect the physics of hearing: the maximized BM amplitude interacts with the cochlear microstructure to generate radial shearing forces that open ion channels in neurosensory hair cells. But the role of perhaps the most characteristic feature of the cochlea, its graded curvature forming a spiral shell, has remained elusive. The long-standing impression is that the spiral shape does not affect hearing, and that the shape facilitates packing the cochlea into a small space. Physical and mathematical models have shown that curvature does not affect maximum amplitude of the BM’s centerline [1‐3], nor shift the maximum amplitude place along the BM [4]. Mammalian behavioral audiograms, however, suggest otherwise. Statistics point at a strong correlation between number of spiral turns and low frequency hearing thresholds [5]. The question arises whether, in studying the effect of curvature, the appropriate physical quantities were examined. Wave energy remains constant as BM waves travel along the cochlear duct, because the change of cochlear dimensions, including curvature, are very slow [6]. Since wave energy is conserved, one could argue that quantities that are averaged over the duct cross-section are also conserved. Wave amplitude at the BM midline may not be affected by curvature, since the midline could be thought of as being close to a cross-sectional average. Curvature, however, has been shown to generate a radial gradient in the fluid pressure [3]. Given that neurosensory cells are stimulated by radial shear forces, it is surprising that radial shear or radial changes in the BM wave amplitude have not been examined in curved models and the mechanics of wave transmission have been studied on straight models instead. In this Letter, we report that cochlear curvature, by redistributing wave energy density across the duct width, enhances radial shearing in the BM region where low frequency sounds are analyzed. We explain energy redistribution by drawing an analogy between wave energy flow and geometric optics. In explaining the ‘‘whispering gallery’’ phenomenon in London’s St. Paul cathedral, Rayleigh [7] showed that a pencil of rays emanating from a source towards a nearby concave boundary would, after any number of reflections, be confined near the boundary. In the cochlea, rays represent wave energy propagation paths reflecting off the concave outer wall. We find, however, that the curvature gradient has an additional role: by reflecting off a wall of decreasing radius of curvature, rays progressively focus on the outer wall, corresponding to an increase in wave energy density. The effect is strongest at the cochlear spiral end (apex), which has the smallest radius of curvature and where low frequency sounds are analyzed. This suggests an effect of the cochlear spiral on low frequency sound perception. To isolate and quantify the effect of curvature on the BM traveling wave, we ignore all geometrical factors other than curvature and BM mass and stiffness. Our simplification extends to considering a BM of constant width (equal to duct width). The fluid is assumed incompressible, irro@� @t � @�

/pdf/cochlea-s-graded-curvature-effect-on-low-frequency-waves-34z3cp1fhf.pdf

Cochlea's graded curvature effect on low frequency waves.

Vasculogenesis and angiogenesis are two different mechanisms for blood vessel formation. Angiogenesis occurs when new vessels sprout from pre-existing vasculature in response to external chemical stimuli. Vasculogenesis occurs via the reorganization of randomly distributed cells into a blood vessel network. Experimental models of vasculogenesis have suggested that the cells exert traction forces onto the extracellular matrix and that these forces may play an important role in the network forming process. In order to study the role of the mechanical and chemical forces in both of these stages of blood vessel formation, we present a mathematical model which assumes that (i) cells exert traction forces onto the extracellular matrix, (ii) the matrix behaves as a linear viscoelastic material, (iii) the cells move along gradients of exogenously supplied chemical stimuli (chemotaxis) and (iv) these stimuli diffuse or are uptaken by the cells. We study the equations numerically, present an appropriate finite difference scheme and simulate the formation of vascular networks in a plane. Our results compare very well with experimental observations and suggest that spontaneous formation of networks can be explained via a purely mechanical interaction between cells and the extracellular matrix. We find that chemotaxis alone is not a sufficient force to stimulate formation of pattern. Moreover, during vessel sprouting, we find that mechanical forces can help in the formation of well defined vascular structures.

/pdf/a-mechanochemical-model-of-angiogenesis-and-vasculogenesis-qsizkeitz8.pdf

A mechanochemical model of angiogenesis and vasculogenesis

Despite its snail-shaped geometry, theoretical studies of the mammalian cochlea generally modeled it as a straight fluid-filled duct. Most people support the idea that the purpose of coiling is to pack the cochlea into a small space. However, attempts by researchers to establish the functional significance of the complex shape of the cochlea have been inconclusive.We study the effects of geometry on fluid loading in the cochlea and introduce helicoidal coordinates in order to describe cochlear geometry and fluid motion. The geometrical description takes into account curvature, partition width, basilar membrane (BM) width, and the height of the modiolus of a guinea pig cochlea. We assume a given mode, wavelength, and amplitude for the BM. We study the fluid equations within the WKB framework and numerically simulate the pressure in a plane containing the modiolar axis. We then compare numerical results for different geometrical parameters.We find that pressure on the BM increases with increasing BM width a...

Daphne Manoussaki

Papers

A mechanical model for the formation of vascular networks in vitro.

The influence of cochlear shape on low-frequency hearing

Cochlea's graded curvature effect on low frequency waves.

A mechanochemical model of angiogenesis and vasculogenesis

Effects of Geometry on Fluid Loading in a Coiled Cochlea