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  1. Ecological models for gene therapy. I. Models for intraorganismal ecology

    Ecological models for gene therapy. I. Models for intraorganismal ecology

    Biological Theory


    We discuss the perspective of intra-organismal ecology by investigating a family of models of niche construction. We consider first and second order models.

    Abstract

    In this article, we discuss the perspective of intraorganismal ecology by investigating a family of ecological models. We consider two types of models. First-order models describe the population dynamics as being directly affected by ecological factors (here understood as nutrients, space, etc). They might be thought of as analogous to Aristotelian physics. Second-order models describe the population dynamics as being indirectly affected, the ecological factors now affecting the derivative of the growth rate (that is, the population acceleration), possibly through an impact on nongenetically inherited factors. Second-order models might be thought of as analogous to Galilean physics. In a companion article, we apply these ideas to a situation of gene therapy.

    Keywords: Ecosystem engineering, Inertial dynamics, Intraorganismal ecology, Niche construction, Nongenetic inheritance

  2. Ecological models for gene therapy. II. Niche construction, nongenetic inheritance, and ecosystem perturbations

    Ecological models for gene therapy. II. Niche construction, nongenetic inheritance, and ecosystem perturbations

    Biological Theory


    We apply the perspective of intra-organismal ecology by investigating a family of ecological models suitable to describe a gene therapy.

    Abstract

    In this article, we apply the perspective of intraorganismal ecology by investigating a family of ecological models suitable to describe a gene therapy for a particular metabolic disorder, the adenosine deaminase deficiency. The gene therapy is modeled as the prospective ecological invasion of an organ (here, bone marrow) by genetically modified stem cells, which then operate niche construction in the cellular environment by releasing an enzyme they synthesize. We show that depending on the order chosen for the model (a choice that cannot be made on a priori assumptions), different kinds of dynamics are expected, possibly leading to different therapeutic strategies. This drives us to discuss several features of the extension of ecology to intraorganismal ecology.

    Keywords: Adenosine deaminase deficiency, Ecosystem engineering, Gene therapy, Intraorganismal ecology, Nongenetic inheritance, Severe combined immunodeficiency

  3. From single cells to tissues: Interactions between the matrix and human breast cells in real time

    From single cells to tissues: Interactions between the matrix and human breast cells in real time

    PLoS ONE


    Bulk properties do not determine shape; however, localized regions of collagen fiber alignment are required for ductal elongation and branching.

    Abstract

    Background: Mammary gland morphogenesis involves ductal elongation, branching, and budding. All of these processes are mediated by stroma - epithelium interactions. Biomechanical factors, such as matrix stiffness, have been established as important factors in these interactions. For example, epithelial cells fail to form normal acinar structures in vitro in 3D gels that exceed the stiffness of a normal mammary gland. Additionally, heterogeneity in the spatial distribution of acini and ducts within individual collagen gels suggests that local organization of the matrix may guide morphogenesis. Here, we quantified the effects of both bulk material stiffness and local collagen fiber arrangement on epithelial morphogenesis. Results: The formation of ducts and acini from single cells and the reorganization of the collagen fiber network were quantified using time-lapse confocal microscopy. MCF10A cells organized the surrounding collagen fibers during the first twelve hours after seeding. Collagen fiber density and alignment relative to the epithelial surface significantly increased within the first twelve hours and were a major influence in the shaping of the mammary epithelium. The addition of Matrigel to the collagen fiber network impaired cell-mediated reorganization of the matrix and increased the probability of spheroidal acini rather than branching ducts. The mechanical anisotropy created by regions of highly aligned collagen fibers facilitated elongation and branching, which was significantly correlated with fiber organization. In contrast, changes in bulk stiffness were not a strong predictor of this epithelial morphology. Conclusions: Localized regions of collagen fiber alignment are required for ductal elongation and branching suggesting the importance of local mechanical anisotropy in mammary epithelial morphogenesis. Similar principles may govern the morphology of branching and budding in other tissues and organs.

    Keywords: Collagens, Morphogenesis, Extracellular matrix, Gels, Anisotropy, Stiffness, Scanning electron microscopy, Mammary gland development

    Citation
    Barnes, C., L. Speroni, K. Quinn, M. Montévil, K. Saetzler, G. Bode-Animashaun, G. McKerr, et al. 2014. “From Single Cells to Tissues: Interactions between the Matrix and Human Breast Cells in Real Time.” Edited by Christophe Egles. PLoS ONE 9 (4): e93325. https://doi.org/10.1371/journal.pone.0093325
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