TGF-beta in the pathology and development of the spine

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DESCRIPTION (provided by applicant): Developmental biology is the study of how cells with specialized functions are derived from undifferentiated cells and how cells interact with each other and their environment to ultimately form tissues and organs. Therefore, it is important to understand the basic mechanisms of development in the skeleton if we are to make progress in engineering skeletal tissue. Members of the TGF-ss superfamily are secreted signaling proteins that regulate many aspects of development and tissue homeostasis including growth, patterning, and cellular differentiation. Polymorphisms and mutations in human Tgfb genes have been associated with pathology in the adult spine and previously, we showed using genetically engineered mouse models that Tgfbr2 is required for development and maintenance of the intervertebral disc (IVD). Our results suggested that 1) TGF-ss is required for boundary formation in the developing axial skeleton and 2) TGF-ss prevents formation of cartilage and promotes the formation of IVD cells in embryonic mesenchyme. In this revision (supplement) application, we will test the hypothesis that gradients of TGF-ss and BMP have threshold effects on mesenchymal progenitors resulting in differentiation along either cartilage or IVD lineages thereby generating a sharp boundary between the two cell types in the axial skeleton. We propose to model TGF-ss mediated boundary formation and the pattern of cellular differentiation in the axial skeleton using a biomimetic self- assembled nanomatrix that can mimic essential properties of natural extracellular matrix (ECM). The nanomatrix is made from a synthetic peptide-amphiphile (PA) and contains the following properties: 1) rapid three-dimensional network formation at physiological conditions 2) cell adhesive moieties to provide cell attachment, and 3) enzyme-mediated degradable sites for matrix remodeling. The nanomatrix can be engineered to contain growth factors throughout the matrix or in a zonal/gradient pattern. Therefore, the nanomatrix can provide an environment that mimics the extracellular matrix (ECM) and can be used as a template for studying tissue development. A clear understanding of how the skeletal system develops will have a direct impact on tissue engineering strategies. Partnerships like this, between developmental biology and bioengineering, will provide a basis for future strategies aimed at disc repair or regeneration.