Nate Huebsch
5th Year Engineering Sciences/MEMP PhD Student
nhuebsch@seas.harvard.edu

Education

B.S. Bioengineering
University of California, Berkeley, 2003

Ph.D. Candidate
Engineering Sciences and Medical Engineering Harvard University School of Engineering and Applied Sciences and Harvard-MIT Division of Health Sciences and Technology, 2004 – present

Research Focus

Cell-Adhesion Ligand Bonds as Mechanosensors

Traditional biomaterials used as implants or for drug delivery are engineered based on their ability to provide mechanical support to tissues or optimize drug transport. New therapies based on stem cell delivery and programming (i.e. Ali et al. Nat Mater 2009) create a need for functionally complex materials designed to interact in a highly controlled manner with specific types of cells. A template for this design challenge is the extracellular matrix (ECM), a protein rich gel surrounding many of the cells in our bodies. Using synthetic materials, bioengineers can fabricate synthetic ECM analogs to systematically study the effects that different aspects of the ECM have on cell behaviors. One exciting result of these studies is that physical characteristics of the ECM, such as its stiffness, have marked affects on a cell fate. However, previous studies in this area have utilized 2D cell culture systems – thus, the extent to which ECM physical properties like rigidity regulate cell fate in physiologically relevant 3D-microenvironments remains unclear.

My research focuses on the mechanisms that stem cells use to sense and ultimately respond to the rigidity of a 3D matrix. Our work shows that the rigidity of 3D matrices regulates stem cell fate – however, in contrast to previous studies done with 2D ECM, we observed almost no correlation between cell fate and cell morphology. Instead, using Förster Resonance Energy Transfer (FRET) and novel biochemical methods, we discovered that matrix rigidity affects molecular scale bond formation between cell adhesion receptors and the ECM. Furthermore, the type of receptors used to bind identical adhesion molecules depended on whether the cells were in a 2D or 3D environment. Altogether, this work suggests that cell-ECM bond formation may be a predominant means for cells to sense matrix rigidity in 3D microenvironments that provide the most accurate model of tissues in the body. Current efforts are aimed at assessing cell-ECM bonds in real-time on the single cell level, to assess the timescales and dynamics of this molecular interaction and gain insight into the intracellular machinery involved.

Publications

• Huebsch ND, Arany PR, Mao AS, Rivera-Feliciano J, Mooney DJ. Extracellular Matrix Mechanics Affect Stem Cell Lineage in 3D by Controlling Integrin Binding. Submitted to Science.
• Ali OA, Huebsch N, Cao L, Dranoff G, Mooney DJ. Programming Cells In-Situ. Nat Mater 2009; 8(2): 151-8.
• Zhao X, Huebsch ND, Mooney DJ, Suo SZ. Controlling Stress-Relaxation Behavior in Hydrogels by Hybrid Crosslinks. In Revision.
• Hsiong SX, Boontheekul T, Huebsch N, Mooney DJ. Cyclic RGD Peptides Enhance 3D Stem Cell Differentiation. Tissue Eng A 2008.
• Hsiong SX, Huebsch N, Fishbach C, Kong HJ, Mooney DJ. Differentiation Stage Regulates Integrin-Adhesion Ligand Bond Formation in RGD Presenting Matrices. Biomacromolecules 2008; 9(7): 1843-51.
• Kong HJ, Kim CJ, Huebsch N, Weitz DA, Mooney DJ. Non-Invasive Probing of the Spatial Organization of Polymer Chains in Hydrogels Using Fluorescence Resonance Energy Transfer (FRET). J Am Chem Soc 2007; 129: 4518-19.
• Huebsch ND, Mooney DJ. Fluorescent Resonance Energy Transfer: A Tool for Probing Molecular Cell-Biomaterial Interactions in Three Dimensions. Biomaterials 2007; 28(15): 2424-37. (Review)
• Huebsch N, Gilbert M, Healy KE. Analysis of Sterilization Protocols for Peptide-Modified Hydrogels. J Biomed Mat Res B. 2005; 74(1): 440-7.
• Patents
• XH Xao, ND Huebsch, SZ Suo, DJ Mooney. On Demand and Reversible Drug Release by External Cue. Filed with Harvard University Patent Office, December 1, 2008.
• Harnessing Cell Dynamics to Engineer Materials. ND Huebsch, DJ Mooney. Filed with Harvard University Patent Office, January 12, 2009.