Paper Number
BB7 

Session
Biomaterials and Biological Systems

Title
Determining the role of tissue inhibitors of metalloproteinases in matrix remodeling during 3D human mesenchymal stem cells motility in cell-degradable hydrogel

Presentation Date and Time
October 11, 2017 (Wednesday) 1:55

Track / Room
Track 1 / Crystal A

Authors (Click on name to view author profile)

1. Daviran, Maryam (Lehigh University, Chemical and Biomolecular Engineering)
2. Longwill, Sarah M. (Lehigh University, Chemical and Biomolecular Engineering)
3. Schultz, Kelly M. (Lehigh University, Chemical and Biomolecular Engineering)

Author and Affiliation Lines (in printed abstract book)
Maryam Daviran, Sarah M. Longwill, and Kelly M. Schultz
Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015

Speaker / Presenter 
Daviran, Maryam

Text of Abstract
Cells actively reengineer and remodel their microenvironment using chemical degradation from cell-secreted enzymes and cellular traction. Specifically, during wound healing human mesenchymal stem cells (hMSCs) migrate from their native tissue to the injury site. A process partially regulated by cell-secreted enzymes. But, little is known about the interplay between the material and the cell during these processes, which has important implications biomaterials design to promote wound healing. Here, we encapsulate hMSCs in peptide-functionalized poly(ethylene glycol) (PEG) hydrogels to characterize cellular remodeling during migration. This hydrogel consists of 4-arm PEG end functionalized with norbornene cross-linked with a matrix metalloproteinase (MMP) degradable peptide. Dynamic cell-mediated scaffold degradation is measured using multiple particle tracking (MPT) microrheology. MPT measures the Brownian motion of fluorescent particles embedded in the hydrogel. Measurements show that prior to motility there is no scaffold degradation directly under the hMSC, allowing the cell to spread and attach. The greatest degradation occurs 160 μm from the cell center, at the end of our measureable window. We hypothesize that hMSCs are secreting a second set of enzymes, tissue inhibitors of metalloproteinases (TIMPs). TIMPs inhibit the activity of the MMPs and, therefore, scaffold degradation. We determine the role of TIMPs by neutralizing them. Four TIMPs have been identified and hMSCs secrete only TIMP-1 and TIMP-2. By inhibiting both TIMPs, hMSCs reverse the degradation profile resulting in a reaction-diffusion gradient; where the greatest degradation is closest to the cells. TIMP inhibition results in upregulation of MMPs that aggressively degrade the matrix. Due to this, cells do not have enough time to spread and attach to the network and instead migrate to stiffer regions. This motility can be harnessed to enhance hMSC delivery to injuries during the wound healing process.