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Authors: Desai, Vivek Dhaval
Advisors: Schwarzbauer, Jean E
Contributors: Molecular Biology Department
Keywords: Adipose-derived mesenchymal stem cells
Growth factors
Wound repair
Subjects: Molecular biology
Issue Date: 2014
Publisher: Princeton, NJ : Princeton University
Abstract: The structural and functional integrity of any tissue is dependent on the proper amount of extracellular matrix (ECM), a complex meshwork of proteins surrounding the cells. Excessive ECM deposition and remodeling during wound repair results in fibrosis, a pathological condition that leads to tissue and organ malfunction. Fibrosis is caused mainly by the unregulated activity of myofibroblasts, highly contractile cells that deposit abundant ECM. To study the modulation of myofibroblast activity, we used human adipose-derived mesenchymal stem cells (ADSCs), which have much potential in regenerative medicine. We found that ADSCs treated with TGF-&beta developed a myofibroblastic phenotype with increases in &alpha-smooth muscle actin (&alpha-SMA), a myofibroblast marker, and ECM proteins type I collagen and fibronectin. In contrast, treatment with bFGF had the opposite effect. bFGF-differentiated ADSCs showed marked down-regulation of &alpha-SMA expression, collagen I, and fibronectin, and loss of focal adhesions and stress fibers. Functionally, bFGF-differentiated ADSCs were significantly more migratory, which correlated with up-regulation of tenascin-C, an anti-adhesive ECM protein, and vimentin, a pro-migratory cytoskeletal protein. On the other hand, TGF-&beta-differentiated ADSCs were significantly more contractile than bFGF-differentiated cells. Interestingly, cells completely reversed their morphologies, marker expression, signaling pathways, and contractility versus migratory profiles when switched from culture with one growth factor to the other, demonstrating that myofibroblast differentiation is not terminal. Cell differentiation was associated with activation of Smad2 downstream of TGF-&beta and of ERK/MAP kinase downstream of bFGF. Reversibility of the TGF-&beta-induced myofibroblastic phenotype depends, in part, on bFGF-induced ERK/MAP kinase signaling. bFGF induces the reversal regardless of the surrounding matrix. These findings show that ADSC differentiation into myofibroblasts and re-differentiation into fibroblast-like cells can be manipulated with growth factors, which may have implications in the development of novel therapeutic strategies to reduce the risk of fibrosis.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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