The Varghese lab studies the interaction of stem cells with extracellular matrix (ECM), with a focus on musculoskeletal tissue regeneration. Her laboratory also investigates the effect of ECM physicochemical cues on disease progression, such as in cancer metastasis and fibrosis. They specialize in engineering materials with specific properties, such as cell adhesivity, self-healing, or on-demand mechanical changes, by manipulating inter- and intramolecular forces.
Among the fascinating novel materials the Varghese group has recently introduced are a self-healing chemically crosslinked hydrogel and a cell-encapsulating hydrogel that bends upon exposure to an electric field. While many self-healing hydrogels had previously been developed, none were permanently crosslinked, so their mechanical weakness limited their practical applications. The Varghese lab’s hydrogel overcomes the challenge of incorporating both permanent and triggerable crosslinks by incorporating pendant polar side chains to mediate hydrogen bonds; these side chains were precisely engineered to interact with those of an adjacent hydrogel surface without interfering with chemical crosslinking. The other dynamic material, an anionic hydrogel that bends in response to an electrical field, is the first to allow independent control of electrical and mechanical bending to direct cell behavior. This system could advance fundamental understanding of how these cues are integrated or in screening drugs that act on mechanosensory cells.
Varghese’s team has developed several improved synthetic materials for specific purposes in musculoskeletal tissue engineering and stem cell culture. These include a hydrogel that promotes mineralization for osteoinduction, discovered by tuning the material’s hydrophobicity; the lab is also pursuing materials to promote muscle and liver formation. To reliably support in vitro growth and self-renewal of human pluripotent stem cells (hPSCs), they have created a material with finely tuned hydrophilicity and elasticity, incorporating a synthetic heparin-mimicking moiety to enhance cells’ exposure to basic fibroblast growth factor (bFGF). Such a material should allow more reproducible maintenance of pluripotency than current methods, which involve feeder cells or biologically-derived ECM.
Modulating surface hydrophobicity controls mesenchymal stem cell (MSC) organization. MSCs cultured on hydrogels composed of acrylamide incorporating amino acids bearing varied numbers of methyl groups: left, 3; right, 5. From Ayala et al., Biomaterials 2011.
Hwang Y, Suk S, Shih YR, Seo T, Du B, Xie Y, Li Z, Varghese S. WNT3A promotes myogenesis of human embryonic stem cells and enhances in vivo engraftment. Sci Rep 2014;4:5916.
Shih Y-RV, Hwang YS, Phadke A, Kang H, Hwang NS, Caro EJ, Nguyen S, Siu M, Theodorakis EA, Gianneschi NC, Vecchio KS, Chien S, Lee OK and Varghese S. Calcium phosphate-bearing matrices induce osteogenic differentiation of stem cells through adenosine signaling. Proc Nat Acad Sci USA 2014; 111(3):990-995.
Phadke A, Zhang C, Arman B, Hsu,CH, Mashelkar RA, Lele AK, Tauber MJ, Arya G, and Varghese S., Rapid self-healing hydrogel. Proc Nat Acad Sci USA 2012; 109(12):4383-4388.