The 'stem cell' concept: is it holding us back?

Developmental biology, regenerative medicine and cancer biology are increasingly occupied with the molecular characterization of stem cells. Yet recent work adds to a growing body of literature suggesting that 'stemness' cannot be reduced to the molecular features of cell types, and is instead an emergent property of cell lineages under feedback control

Regulatory feedback on receptor and non-receptor synthesis for robust signaling.

Elaborate regulatory feedback processes are thought to make biological development robust, that is, resistant to changes induced by genetic or environmental perturbations. How this might be done is still not completely understood. Previous numerical simulations on reaction-diffusion models of Dpp gradients in Drosophila wing imaginal disc have showed that feedback (of the Hill function type) on (signaling) receptors and/or non-(signaling) receptors are of limited effectiveness in promoting robustness. Spatial nonuniformity of the feedback processes has also been shown theoretically to lead to serious shape distortion and a principal cause for ineffectiveness. Through mathematical modeling and analysis, the present article shows that spatially uniform nonlocal feedback mechanisms typically modify gradient shape through a shape parameter (that does not change with location). This in turn enables us to uncover new multi-feedback instrument for effective promotion of robust signaling gradients

Hierarchical Lattice Models of Hydrogen Bond Networks in Water

We develop a graph-based model of the hydrogen bond network in water, with a view towards quantitatively modeling the molecular-level correlational structure of the network. The networks are formed are studied by the constructing the model on two infinite-dimensional lattices. Our models are built \emph{bottom up}, based on microscopic information coming from atomistic simulations, and we show that the predictions of the model are consistent with known results from ab-initio simulations of liquid water. We show that simple entropic models can predict the correlations and clustering of local-coordination defects around tetrahedral waters observed in the atomistic simulations. We also find that orientational correlations between bonds are longer ranged than density correlations, and determine the directional correlations within closed loops and show that the patterns of water wires within these structures are also consistent with previous atomistic simulations. Our models show the existence of density and compressibility anomalies, as seen in the real liquid, and the phase diagram of these models is consistent with the singularity-free scenario previously proposed by Sastry and co-workers (Sastry et al, PRE 53, 6144 (1996)).Comment: 17 pages, published versio

Glypican-1 controls brain size through regulation of fibroblast growth factor signaling in early neurogenesis

<p>Abstract</p> <p>Background</p> <p>Cell surface heparan sulfate proteoglycans (HSPGs) act as co-receptors for multiple families of growth factors that regulate animal cell proliferation, differentiation and patterning. Elimination of heparan sulfate during brain development is known to produce severe structural abnormalities. Here we investigate the developmental role played by one particular HSPG, glypican-1 (Gpc1), which is especially abundant on neuronal cell membranes, and is the major HSPG of the adult rodent brain.</p> <p>Results</p> <p>Mice with a null mutation in <it>Gpc1 </it>were generated and found to be viable and fertile. The major phenotype associated with <it>Gpc1 </it>loss is a highly significant reduction in brain size, with only subtle effects on brain patterning (confined to the anterior cerebellum). The brain size difference emerges very early during neurogenesis (between embryonic days 8.5 and 9.5), and remains roughly constant throughout development and adulthood. By examining markers of different signaling pathways, and the differentiation behaviors of cells in the early embryonic brain, we infer that <it>Gpc1</it>^-/-phenotypes most likely result from a transient reduction in fibroblast growth factor (FGF) signaling. Through the analysis of compound mutants, we provide strong evidence that Fgf17 is the FGF family member through which Gpc1 controls brain size.</p> <p>Conclusion</p> <p>These data add to a growing literature that implicates the glypican family of HSPGs in organ size control. They also argue that, among heparan sulfate-dependent signaling molecules, FGFs are disproportionately sensitive to loss of HSPGs. Finally, because heterozygous <it>Gpc1 </it>mutant mice were found to have brain sizes half-way between homozygous and wild type, the data imply that endogenous HSPG levels quantitatively control growth factor signaling, a finding that is both novel and relevant to the general question of how the activities of co-receptors are exploited during development.</p

A Calculus of Purpose

Biological systems are so complex that we must ask: "What purpose does all this complexity serve?" Lander argues that computational biology may help provide answer

Optimal experimental design for mathematical models of haematopoiesis.

The haematopoietic system has a highly regulated and complex structure in which cells are organized to successfully create and maintain new blood cells. It is known that feedback regulation is crucial to tightly control this system, but the specific mechanisms by which control is exerted are not completely understood. In this work, we aim to uncover the underlying mechanisms in haematopoiesis by conducting perturbation experiments, where animal subjects are exposed to an external agent in order to observe the system response and evolution. We have developed a novel Bayesian hierarchical framework for optimal design of perturbation experiments and proper analysis of the data collected. We use a deterministic model that accounts for feedback and feedforward regulation on cell division rates and self-renewal probabilities. A significant obstacle is that the experimental data are not longitudinal, rather each data point corresponds to a different animal. We overcome this difficulty by modelling the unobserved cellular levels as latent variables. We then use principles of Bayesian experimental design to optimally distribute time points at which the haematopoietic cells are quantified. We evaluate our approach using synthetic and real experimental data and show that an optimal design can lead to better estimates of model parameters

Growth factor–induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells

The cell surface heparan sulfate proteoglycan (HSPG) glypican-1 is up-regulated by pancreatic and breast cancer cells, and its removal renders such cells insensitive to many growth factors. We sought to explain why the cell surface HSPG syndecan-1, which is also up-regulated by these cells and is a known growth factor coreceptor, does not compensate for glypican-1 loss. We show that the initial responses of these cells to the growth factor FGF2 are not glypican dependent, but they become so over time as FGF2 induces shedding of syndecan-1. Manipulations that retain syndecan-1 on the cell surface make long-term FGF2 responses glypican independent, whereas those that trigger syndecan-1 shedding make initial FGF2 responses glypican dependent. We further show that syndecan-1 shedding is mediated by matrix metalloproteinase-7 (MMP7), which, being anchored to cells by HSPGs, also causes its own release in a complex with syndecan-1 ectodomains. These results support a specific role for shed syndecan-1 or MMP7–syndecan-1 complexes in tumor progression and add to accumulating evidence that syndecans and glypicans have nonequivalent functions in vivo

Plasticity of the cis-Regulatory Input Function of a Gene

The transcription rate of a gene is often controlled by several regulators that bind specific sites in the gene's cis-regulatory region. The combined effect of these regulators is described by a cis-regulatory input function. What determines the form of an input function, and how variable is it with respect to mutations? To address this, we employ the well-characterized lac operon of Escherichia coli, which has an elaborate input function, intermediate between Boolean AND-gate and OR-gate logic. We mapped in detail the input function of 12 variants of the lac promoter, each with different point mutations in the regulator binding sites, by means of accurate expression measurements from living cells. We find that even a few mutations can significantly change the input function, resulting in functions that resemble Pure AND gates, OR gates, or single-input switches. Other types of gates were not found. The variant input functions can be described in a unified manner by a mathematical model. The model also lets us predict which functions cannot be reached by point mutations. The input function that we studied thus appears to be plastic, in the sense that many of the mutations do not ruin the regulation completely but rather result in new ways to integrate the inputs

Discovery of a Novel Molecule that Regulates Tumor Growth and Metastasis

The heparan sulfate proteoglycan, Glypican-1 (GPC1), significantly impacts the growth of pancreatic cancer cells in vivo and markedly attenuates tumor angiogenesis and metastasis in athymic mice. Interestingly, both cancer cell-derived and host-derived GPC1 play an important role in tumor development and spread. These data suggest that GPC1 may be a valid therapeutic target for pancreatic cancer. KEYWORDS: Glypican-1, GPC1, pancreatic cancer, PDAC, angiogenesis, metastasis, tumor growth, microenvironment Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic and biologically aggressive malignancy that is the fourth leading cause of cancer death in the U.S. with a 5-year survival rate of less than 5%. Since PDAC is usually diagnosed at an advanced stage, after the tumor has already metastasized and is no longer operable, the number of new PDAC cases diagnosed each year is nearly equivalent to the mortality rate In a recent study published in the Journal of Clinical Investigation, it was shown that a common growth factor coreceptor, Glypican-1 (GPC1), is abnormally abundant in pancreatic cancer and that the loss of GPC1 results in reduced tumor growth, angiogenesis, and metastasi