The extracellular environment has significant, but largely uncharacterized, involvement in function of the central nervous system. Biomaterials can be engineered to present defined microenvironments that can greatly simplify the experimental variability in biological systems so that effects of a single variable can be experimentally isolated in vitro. In addition, through systematic manipulation of different microenvironmental features presented by the biomaterial, we can identify which aspects of a cell's surroundings instrumentally contribute to specific pathologies and apply this knowledge to develop new clinical therapies that act by locally altering the extracellular environment. In particular, we aim to use biomaterial tools to identify key physiological interactions between cells and their environment during central nervous system tissue development, repair, and disease progression. Identification of crucial alterations in these interactions will lead to impactful mechanistic discoveries and ultimately new clinical strategies based on controlled manipulation of these interactions.
Biomaterial Constructs to Characterize the Role of Extracellular Matrix in Glioblastoma Multiforme
There is a large body of evidence that suggests that the unique extracellular environment in the brain, which contains few fibrous proteins and high amounts of hyaluronic acid, is responsible for the characteristic aggressiveness and resistance to conventional treatments observed in brain tumors categorized as glioblastoma mulitforme. However the specific interactions between tumor cells and the extracellular matrix and their relationship to tumor physiology are largely unknown. In general, these mechanisms have been challenging to elucidate, in part because of the lack of physiologically translatable models that can be studied in vitro. Thus, we are developing hyaluronic acid-based hydrogels as ex vivo culture systems that can be tuned to mimic the native microenvironment in healthy and glioblastoma-affected brain. HA and its cell surface receptors are dramatically upregulated in the microenvironment of glioblastoma and this shift likely has a substantial contributes to the increased the migratory capacity and resistance to chemotherapeutic drugs. Furthermore, glioblastoma cells cultured within 3D environments, and particularly those containing hyaluronic acid, more closely mirror the in vivo tumor physiology than when cells are cultured using standard techniques. Notably, the biochemical and biophysical landscape presented to encapsulated cells can be precisely and independently controlled to enable investigations of the quantitative effects of these features on cell physiology so that clinically relevant data can be acquired in an ex vivo setting. Our research aims to 1) fully characterize the extracellular matrix in tissues isolated from clinical glioblastomas and 2) optimize microenvironmental features presented by hydrogels to best recapitulate the in vivo tumor niche in 3D cultures of patient-derived glioblastoma cells. This project is in collaboration with Dr. David Nathanson, Assistant Professor in Medical and Molecular Pharmacology at UCLA.
Development of Biomaterial Systems that Drive Oligodendrocyte Differentiation
Because of our limited understanding of the highly complex cell-cell and cell-matrix interactions in the central nervous system and how these interactions coordinate tissue function, it has been necessary to use intensive in vivo animal models almost exclusively. Thus, new clinical treatments have been slow to appear. As the in vivo behavior of neural stem/progenitor cells often deviates greatly from that observed in vitro using traditional methods, our research aims to develop ex vivo culture environments that mimic the geometrical, mechanical and chemical features of the native extracellular matrix to facilitate basic and translational neuroscience research. The ability to finely tune the presentation of these cues within a modular platform will enable ex vivo investigation of cell-matrix interactions within conditions that approximate those in vivo so that physiologically relevant data can be obtained in a simplified context. Identification of essential cell-ECM interactions as therapeutic targets will be greatly facilitated by acquiring high-throughput data to screen for key interactions that mediate re-myelination by newly differentiated oligodendrocytes. Ultimately, we aim to translate these microenvironments in vivo as therapies that directly alter the inhibitory environment that develops with chronic inflammation in the central nervous system.