Unraveling the Impact of Extracellular Matrix on Stem Cell Commitment and Fibrosis
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Thursday, February 4, 2016 - 4:30pm
Reciprocal interactions of cells with their microenvironment are fundamental to multiple cellular processes necessary for tissue development, homeostasis, and regeneration. It is becoming increasingly apparent that while the extracellular environment normally maintains tissue homeostasis, but when negatively perturbed, it may also contribute to disease progression and age-dependent pathologies. However, it is still unknown how the extracellular matrix contributes to tissue regeneration and how changes in the extracellular matrix induces differential cellularresponses in diseases. In this talk, I will discuss our efforts to delineate the role of the extracellular matrix on cellular responses relevant to tissue repair, stem cell differentiation, and disease progression.
First, I will talk about a biomineralized matrix that we have developed through a biomimetic approach. This matrix emulating the calcium phosphate (CaP)-rich bone microenvironment can be used to treat critical bone defects, as it recruits endogenous cells to form vascularized bone tissues. This biomimetic matrix also allowed us to examine the molecular mechanism by which CaP minerals induce osteogenesis of stem cells, while inhibiting their adipogenesis. Our studies show that extracellular phosphate uptake through SLC20a1 supports osteogenesis viaadenosine, an ATP metabolite, which acts as an autocrine/paracrine signaling molecule through A2b adenosine receptor.
I will next talk about our recent efforts on understanding the role of matrix cues on fibrosis. Fibrosis is a pervasive disease in which the excessive deposition of extracellular matrix (ECM) compromises tissue function. Although the underlying mechanisms are mostly unknown, altered matrix properties have been proposed as a contributor to fibrosis rather than merely a manifestation of the disease. Here, I will discuss the contribution of elastic fibers, an ECM component, on fibrosis. We show that loss of fibulin-5, a matricellular protein that contributes to elastic fiber assembly, not only decreases tissue stiffness, but also diminishes the inflammatory response and abrogates the fibrotic phenotype in a mouse model of cutaneous fibrosis. Increasing the matrix stiffness raises the inflammatory response above a threshold level, independent of TGF-β, to stimulate further ECM secretion from fibroblasts and advance the progression of fibrosis.
I will end by briefly introducing our efforts to develop vascularized tissue and healthy and disease tissue models in vitro as a technological platforms to study basic concepts and screen drug and small molecules.
1. Shih Y-RV et al., “Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling” PNAS 111: 990 (2014)
2. Kang H et al., “Mineralized gelatin methacrylate-based matrices induce osteogenic differentiation of human induced pluripotent stem cells” Acta Biomaterialia 10: 4961 (2014)
3. Kang H et al., “Biomineralized matrices dominate soluble cues to direct osteogenic differentiation of human mesenchymal stem cells through adenosine signaling” Biomacromolecules 16: 1050 (2015)
4. Nakasaki M et al., “The matrix protein Fibulin-5 lies at the interface of tissue stiffness and inflammation in fibrosis” Nature Communications (in press)
Shyni Varghese, Ph.D. is an Associate Professor of Bioengineering at University of California, San Diego. Dr. Varghese’s research focuses at the interface of biologically inspired materials and stem cells. Dr. Varghese has co-authored over 80 peer reviewed research articles, covering a wide range of interdisciplinary topics in stem cells, smart biomaterials, biologically inspired systems, and regenerative medicine. Her research activities have also resulted in over 12 patent disclosures. Examples of ongoing research activities in her laboratory involve developing: functional biomaterials such as self-healing materials, technologies to improve stem cell based therapies including activating endogenous stem cells, engineered functional tissue grafts, and organ-on-a-chip systems. She is on the editorial board of a number of journals and a consultant to various biotech companies.