Stem cells have the remarkable ability to develop into a range of functional cell types of the adult body that can be used to repair damaged or diseased tissues. Despite advances in achieving selective differentiation in the laboratory, controlling the fate of stem cells post-transplantation still remains an unsolved challenge and a significant obstacle to the use of stem cells as therapeutics. Stem cell specification during development is orchestrated by the concerted action of morphogens, such as growth factors, which initiate intracellular signaling cascades activating gene transcription. Glycans populating surfaces of stem cells play a key role in regulating the interactions of growth factors with their cognate receptors; however, their regulatory functions have been largely unexplored in the context of achieving selectivity in differentiation. The objective of the proposed projects is to create new techniques for manipulating glycan structures at the surface of stem cells to tune the association of endogenous growth factors at the cell-matrix interface in vivo. Two distinct approaches are proposed to achieve this goal. The first approach describes priming of the stem cell surface prior to transplantation with nanoscale glycomimetic materials with affinity for a growth factor of interest. Once the remodeled cells are delivered to a tissue, these materials will promote the association of the endogenous growth factor and activate signaling and differentiation. The second approach outlines the targeted delivery of these materials to the surface of stem cells in vivo concomitant with the inhibition of glycan production in these cells. This in situ remodeling will allow us to temporarily override native glycan signals at a critical junction to achieve selective activation of growth factor signaling and a desired differentiation outcome. This work will provide a novel solution to a key problem in the field of regenerative medicine and will open new opportunities for exploration of the rich biology of glycans for applications in stem cell technologies, tissue engineering and biomedicine.
Stem cell therapies promise to fundamentally transform the practice of medicine in the 21st century. Realizing the promise of stem cells will, however, require achieving control over their differentiation after transplantation into lineages with therapeutic potential. This proposal seeks to develop strategies that target glycans at the surfaces of stem cells to promote their interactions with morphogens and to guide their differentiation in vivo.
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