Cellular and Molecular Bioengineering

, Volume 8, Issue 4, pp 530–542 | Cite as

Haptotaxis is Cell Type Specific and Limited by Substrate Adhesiveness

  • Jessica H. Wen
  • Onkiu Choi
  • Hermes Taylor-Weiner
  • Alexander Fuhrmann
  • Jerome V. Karpiak
  • Adah Almutairi
  • Adam J. EnglerEmail author


Motile cells navigate through tissue by relying on tactile cues from gradients provided by extracellular matrix such as ligand density or stiffness. Mesenchymal stem cells (MSCs) and fibroblasts encounter adhesive or ‘haptotactic’ gradients at the interface between healthy and fibrotic tissue as they migrate towards an injury site. Mimicking this phenomenon, we developed tunable RGD and collagen gradients in polyacrylamide hydrogels of physiologically relevant stiffness using density gradient multilayer polymerization to better understand how such ligand gradients regulate migratory behaviors. Independent of ligand composition and fiber deformation, haptotaxis was observed in mouse 3T3 fibroblasts. Human MSCs however, haptotaxed only when cell-substrate adhesion was indirectly reduced via addition of free soluble matrix ligand mimetic peptides. Under basal conditions, MSCs were more contractile than fibroblasts. However, the presence of soluble adhesive peptides reduced MSC-induced substrate deformations; increased contractility may contribute to limited migration, but modulating cytoskeletal assembly was ineffective at promoting MSC haptotaxis. When introduced to gradients of increased absolute ligand concentrations, 3T3s displayed increased contractility and no longer haptotaxed. These data suggest that haptotactic behaviors are limited by adhesion and that although both cell types may home to tissue to aid in repair, fibroblasts may be more responsive to ligand gradients than MSCs.


Migration Mesenchymal stem cell Fibroblast Ligand gradient Surface modification Elasticity 



This work was supported by grants from the National Institutes of Health (DP2OD006460 to A.J.E.), National Science Foundation (1463689 to A.J.E.), and the National Science Foundation Graduate Research Fellowship Program (to J.H.W. and H.T.-W.). The authors declare no commercial affiliations or conflicts of interest.

Conflict of interest

Jessica H. Wen, Onkiu Choi, Hermes Taylor-Weiner, Alexander Fuhrmann, Jerome V. Karpaik, Adah Almutairi, and Adam J. Engler declare that they have no conflicts of interest related to this work.

Ethical Standards

No human studies were carried out by the authors for this article. No animal studies were carried out by the authors for this article.

Supplementary material

12195_2015_398_MOESM1_ESM.tif (5.5 mb)
Supp. Figure 1. Cell Spread Area and Attachment on Collagen Gradients. Dots indicate the distribution of cell spread areas, and grey bars indicate the number of cells found across the gradient region of a surface collagen density gradient substrate 15 h post-seeding.. Supplementary material 1 (TIFF 5643 kb)
12195_2015_398_MOESM2_ESM.tif (24.6 mb)
Supp. Figure 2. Characterization of MSC Migration on Collagen Gradients. A. Rose plots of MSC migratory paths beginning at the origin on low, gradient, and high collagen density regions of PA-AA hydrogels. B. Tactic index, or the ratio of displacement to total distance traveled by cells on low, gradient, and high collagen density regions of PA-AA hydrogels. Each data point indicates one cell. (mean ± S.E.M.). C. Histograms depicting initial to final position displacement vector angles of MSCs on low, gradient, and high collagen density regions of PA-AA hydrogels. 0 angle indicates migration directly up the ligand gradient. Supplementary material 2 (TIFF 25222 kb)
12195_2015_398_MOESM3_ESM.tif (27.9 mb)
Supp. Figure 3. Characterization of 3T3 Migration on Collagen Gradients. A. Rose plots of 3T3 migratory paths beginning at the origin on low, gradient, and high collagen density regions of PA-AA hydrogels. B. Tactic index, or the ratio of displacement to total distance traveled by cells on low, gradient, and high collagen density regions of PA-AA hydrogels. Each data point indicates one cell. (mean ± S.E.M.; ***p < 0.005). C. Histograms depicting initial to final position displacement vector angles of 3T3 s on low, gradient, and high collagen density regions of PA-AA hydrogels. 0 angle indicates migration directly up the ligand gradient. Supplementary material 3 (TIFF 28570 kb)
12195_2015_398_MOESM4_ESM.tif (8.3 mb)
Supp. Figure 4. Effect of Drug Treatment on 3T3 Migration Paths. A. Rose plots of migratory paths beginning at the origin on the gradient region of PA-PEG-RGD hydrogels with RGD gradients of 3T3 s treated with lysophosphatidic acid, bradykinin, nocodazole, and cytochalasin D. B. Rose plots of migratory paths beginning at the origin on the gradient region of PA-AA hydrogels with collagen gradients of 3T3 s treated with lysophosphatidic acid. Supplementary material 4 (TIFF 8495 kb)
12195_2015_398_MOESM5_ESM.tif (4.7 mb)
Supp. Figure 5. Fibronectin FRET Intensity Characterization. FRET intensity ratio map of a blebbistatin treated cell (left) and an untreated cell (center), and measured FRET intensity ratio of undeformed protein underneath a blebbistatin treated cell and an untreated cell (right) seeded on a polyacryalmide hydrogels (right). (n = 8; ***p < 0.005). Supplementary material 5 (TIFF 4801 kb)


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Copyright information

© Biomedical Engineering Society 2015

Authors and Affiliations

  • Jessica H. Wen
    • 1
  • Onkiu Choi
    • 2
  • Hermes Taylor-Weiner
    • 1
  • Alexander Fuhrmann
    • 1
  • Jerome V. Karpiak
    • 3
  • Adah Almutairi
    • 3
    • 4
  • Adam J. Engler
    • 1
    • 5
    Email author
  1. 1.Department of BioengineeringUC San DiegoLa JollaUSA
  2. 2.Department of Biomedical EngineeringNational Yang-Ming UniversityTaipei CityTaiwan
  3. 3.Department of Biomedical SciencesUC San DiegoLa JollaUSA
  4. 4.Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of CaliforniaLa JollaUSA
  5. 5.Sanford Consortium for Regenerative MedicineLa JollaUSA

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