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Fiber Stretch and Reorientation Modulates Mesenchymal Stem Cell Morphology and Fibrous Gene Expression on Oriented Nanofibrous Microenvironments

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Abstract

Because differentiation of mesenchymal stem cells (MSCs) is enacted through the integration of soluble signaling factors and physical cues, including substrate architecture and exogenous mechanical stimulation, it is important to understand how micropatterned biomaterials may be optimized to enhance differentiation for the formation of functional soft tissues. In this work, macroscopic strain applied to MSCs in an aligned nanofibrous microenvironment elicited cellular and nuclear deformations that varied depending on scaffold orientation. Reorientation of aligned, oriented MSCs corresponded at the microscopic scale with the affine approximation of their deformation based on macroscopic strains. Moreover, deformations at the subcellular scale corresponded with scaffold orientation, with changes in nuclear shape depending on the direction of substrate alignment. Notably, these deformations induced changes in gene expression that were also dependent on scaffold and cell orientations. These findings demonstrate that directional biases in substrate microstructure convey direction-dependent mechanosensitivity to MSCs and provide an experimental framework in which to explore the mechanistic underpinnings of this response.

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References

  1. Baker, B. M., and R. L. Mauck. The effect of nanofiber alignment on the maturation of engineered meniscus constructs. Biomaterials 28(11):1967–1977, 2007.

    Article  PubMed  CAS  Google Scholar 

  2. Baker, B. M., A. S. Nathan, A. O. Gee, and R. L. Mauck. The influence of an aligned nanofibrous topography on human mesenchymal stem cell fibrochondrogenesis. Biomaterials 31(24):6190–6200, 2010.

    Article  PubMed  CAS  Google Scholar 

  3. Baker, B. M., A. S. Nathan, G. R. Huffman, and R. L. Mauck. Tissue engineering with meniscus cells derived from surgical debris. Osteoarthr Cartil 17(3):336–345, 2009.

    Article  PubMed  CAS  Google Scholar 

  4. Baker, B. M., N. L. Nerurkar, J. A. Burdick, D. M. Elliott, and R. L. Mauck. Fabrication and modeling of dynamic multi-polymer nanofibrous scaffold. J. Biomech. Eng. 131(10):101012, 2009.

    Article  PubMed  Google Scholar 

  5. Baker, B. M., S. P. Shah, A. H. Huang, and R. L. Mauck. Dynamic tensile loading improves the functional properties of mesenchymal stem cell-laden nanofiber-based fibrocartilage. Tissue Eng. Part A 17(9):1–11, 2011.

    Article  Google Scholar 

  6. Bruehlmann, S. B., P. A. Hulme, and N. A. Duncan. In situ intercellular mechanics of the bovine outer annulus fibrosus subjected to biaxial strains. J. Biomech. 37(2):223–231, 2004.

    Article  PubMed  Google Scholar 

  7. Bruehlmann, S. B., J. R. Matyas, and N. A. Duncan. Collagen fibril sliding governs cell mechanics in the anulus fibrosus: an in situ confocal microscopy study of bovine discs. Spine 29(23):2612–2620, 2004.

    Article  PubMed  Google Scholar 

  8. Connelly, J. T., A. J. Garcia, and M. E. Levenston. Inhibition of in vitro chondrogenesis in RGD-modified three-dimensional alginate gels. Biomaterials 28:1071–1083, 2007.

    Article  PubMed  CAS  Google Scholar 

  9. Dahl, K. N., E. A. Booth-Gauthier, B. Ladoux, et al. In the middle of it all: mutual mechanical regulation between the nucleus and the cytoskeleton. J. Biomech. 43(1):2–8, 2009.

    Article  PubMed  Google Scholar 

  10. Dahl, K. N., S. M. Kahn, K. L. Wilson, and D. E. Discher. The nuclear envelope lamina network has elasticity and a compressibility limit suggestive of a molecular shock absorber. J. Cell Sci. 117:4779–4786, 2004.

    Article  PubMed  CAS  Google Scholar 

  11. Dahl, K. N., A. J. Ribeiro, and J. Lammerding. Nuclear shape, mechanics, and mechanotransduction. Circ. Res. 102(11):1307–1318, 2008.

    Article  PubMed  CAS  Google Scholar 

  12. Discher, D. E., D. J. Mooney, and P. W. Zandstra. Growth factors, matrices, and forces combine and control stem cells. Science 324:1673–1677, 2009.

    Article  PubMed  CAS  Google Scholar 

  13. Driscoll, T. D., N. L. Nerurkar, N. T. Jacobs, D. M. Elliott, and R. L. Mauck. Shear mechanics of electrospun scaffold for annulus fibrosus tissue engineering. J. Mech. Behav. Biomed. Mater. (in press).

  14. Engler, A. J., S. Sen, H. L. Sweeney, and D. E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689, 2006.

    Article  PubMed  CAS  Google Scholar 

  15. Huang, A. H., M. J. Farrell, M. Kim, and R. L. Mauck. Long-term dynamic loading improves the mechanical properties of chondrogenic mesenchymal stem cell-laden hydrogels. Eur. Cell. Mater. 19:72–85, 2010.

    PubMed  CAS  Google Scholar 

  16. Huang, A. H., A. Stein, and R. L. Mauck. The complex transcriptional topography of mesenchymal stem cell chondrogenesis for cartilage tissue engineering. Tissue Eng. Part A 16(9):2699–2708, 2010.

    Article  PubMed  CAS  Google Scholar 

  17. Kurpinski, K., J. Chu, C. Hashi, and S. Li. Anisotropic mechanosensing by mesenchymal stem cells. Proc. Natl Acad. Sci. USA 103(44):16095–16100, 2006.

    Article  PubMed  CAS  Google Scholar 

  18. Lake, S. P., K. S. Miller, D. M. Elliott, and L. J. Soslowsky. Effect of fiber distribution and realignment on the nonlinear and inhomogeneous mechanical properties of human supraspinatus tendon under longitudinal tensile loading. J. Orthop. Res. 27(12):1596–1602, 2009.

    Article  PubMed  Google Scholar 

  19. Li, Y., J. S. Chu, K. Kurpinski, X. Li, D. M. Bautista, L. Yang, K. L. Paul Sung, and S. Li. Biophysical regulation of histone acetylation in mesenchymal stem cells. Biophys. J. 100(8):1902–1909, 2011.

    Article  PubMed  CAS  Google Scholar 

  20. Li, W. J., R. L. Mauck, J. A. Cooper, X. Yuan, and R. S. Tuan. Engineering controllable anisotropy in electrospun biodegradable nanofibrous scaffolds for musculoskeletal tissue engineering. J. Biomech. 40(8):1686–1693, 2007.

    Article  PubMed  Google Scholar 

  21. Lynch, H. A., W. Johannessen, J. P. Wu, A. Jawa, and D. M. Elliott. Effect of fiber orientation and strain-rate on the uniaxial tensile material properties of tendon. J. Biomech. Eng. 125:726–731, 2003.

    Article  PubMed  Google Scholar 

  22. Marchand, F., and A. M. Ahmed. Investigation of the laminate structure of lumbar disc anulus fibrosus. Spine 15:402–410, 1990.

    Article  PubMed  CAS  Google Scholar 

  23. Mauck, R. L., B. M. Baker, N. L. Nerurkar, J. A. Burdick, W. J. Li, R. S. Tuan, and D. M. Elliott. Engineering on the straight and narrow: the mechanics of nanofibrous assemblies for fiber-reinforced. Tissue Eng. Part B Rev. 15:171–193, 2009.

    Article  PubMed  CAS  Google Scholar 

  24. Mauck, R. L., X. Yuan, and R. S. Tuan. Chondrogenic differentiation and functional maturation of bovine mesenchymal stem cells in long-term agarose culture. Osteoarthr Cartil 14(2):179–189, 2006.

    Article  PubMed  CAS  Google Scholar 

  25. McBeath, R., D. M. Pirone, C. M. Nelson, K. Bhadriraju, and C. S. Chen. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell. 6(4):483–495, 2004.

    Article  PubMed  CAS  Google Scholar 

  26. Moffat, K. L., A. S. Kwei, J. P. Spalazzi, S. B. Doty, W. N. Levine, and H. H. Lu. Novel nanofiber-based scaffold for rotator cuff repair and augmentation. Tissue Eng. Part A 15(1):115–126, 2009.

    Article  PubMed  CAS  Google Scholar 

  27. Mow, V. C., and R. Huiskes. Basic Orthopaedic Biomechanics and Mechanobiology. Philadelphia, PA: Lippincott Williams & Wilkins, 1991.

    Google Scholar 

  28. Nathan, A. S., B. M. Baker, N. L. Nerurkar, and R. L. Mauck. Mechano-topographic modulation of stem cell nuclear shape on nanofibrous scaffolds. Acta Biomater. 7(1):57–66, 2011.

    Article  PubMed  CAS  Google Scholar 

  29. Nerurkar, N. L., B. M. Baker, S. Sen, E. E. Wible, D. M. Elliott, and R. L. Mauck. Nanofibrous biologic laminates replicate the form and function of the annulus fibrosus. Nat. Mater. 8(12):986–992, 2009.

    Article  PubMed  CAS  Google Scholar 

  30. Nerurkar, N. L., D. M. Elliott, and R. L. Mauck. Mechanics of oriented electrospun nanofibrous scaffolds for annulus fibrosus tissue engineering. J. Orthop. Res. 25(8):1018–1028, 2007.

    Article  PubMed  CAS  Google Scholar 

  31. Nerurkar, N. L., R. L. Mauck, and D. M. Elliott. ISSLS prize winner: integrating theoretical and experimental methods for functional tissue engineering of the annulus fibrosus. Spine 33(25):2691–2701, 2008.

    Article  PubMed  Google Scholar 

  32. Nerurkar, N. L., R. L. Mauck, and D. M. Elliott. Modeling interlamellar interactions in angle-ply biologic laminates for annulus fibrosus tissue engineering. Biomech. Model Mechanobiol. doi:10.1007/s10237-011-0288-0, 2011.

  33. Nerurkar, N. L., S. Sen, A. H. Huang, D. M. Elliott, and R. L. Mauck. Engineered disc-like angle-ply structures for intervertebral disc replacement. Spine 35(8):867–873, 2010.

    Article  PubMed  Google Scholar 

  34. Nesti, L. J., W. J. Li, R. M. Shanti, Y. J. Jiang, W. Jackson, B. A. Freedman, T. R. Kuklo, J. R. Giuliani, and R. S. Tuan. Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. Tissue Eng. Part A 14(9):1527–1537, 2008.

    Article  PubMed  CAS  Google Scholar 

  35. Peltz, C. D., S. M. Perry, C. L. Getz, and L. J. Soslowsky. Mechanical properties of the long-head of the biceps tendon are altered in the presence of rotator cuff tears in a rat model. J. Orthop. Res. 27(3):416–420, 2009.

    Article  PubMed  Google Scholar 

  36. Petrie, T. A., J. E. Raynor, D. W. Dumbauld, T. T. Lee, S. Jagtap, K. L. Templeman, D. M. Collard, and A. J. Garcia. Multivalent integrin-specific ligands enhance tissue healing and biomaterial integration. Sci. Transl. Med. 2(45):45ra60, 2010.

    Article  PubMed  Google Scholar 

  37. Pittenger, M. F., A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig, and D. R. Marshak. Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147, 1999.

    Article  PubMed  CAS  Google Scholar 

  38. Stella, J. A., J. Liao, Y. Hong, W. David Merryman, W. R. Wagner, and M. S. Sacks. Tissue-to-cellular level deformation coupling in cell-microintegrated elastomeric scaffolds. Biomaterials 29(22):3228–3236, 2008.

    Article  PubMed  CAS  Google Scholar 

  39. Stella, J. A., W. R. Wagner, and M. S. Sacks. Scale-dependent fiber kinematics of elastomeric electrospun scaffolds for soft tissue engineering. J. Biomed. Mater. Res. A 93(3):1032–1042, 2010.

    PubMed  Google Scholar 

  40. Thomas, C. H., J. H. Collier, C. S. Sfeir, and K. E. Healy. Engineering gene expression and protein synthesis by modulation of nuclear shape. Proc. Natl Acad. Sci. USA 99(4):1972–1977, 2002.

    Article  PubMed  CAS  Google Scholar 

  41. Upton, M. L., C. L. Gilchrist, F. Guilak, and L. A. Setton. Transfer of macroscale tissue strain to microscale cell regions in the deformed meniscus. Biophys. J. 95(4):2116–2124, 2008.

    Article  PubMed  CAS  Google Scholar 

  42. Webster, M., K. L. Witkin, and O. Cohen-Fix. Sizing up the nucleus: nuclear shape, size and nuclear envelope assembly. J. Cell Sci. 122:1970–1978, 2009.

    Article  Google Scholar 

  43. Xie, J., X. Li, J. Lipner, C. N. Manning, A. G. Schwartz, S. Thomopoulos, and Y. Xia. “Aligned-to-random” nanofiber scaffolds for mimicking the structure of the tendon-to-bone insertion site. Nanoscale 2(6):923–926, 2010.

    Article  PubMed  CAS  Google Scholar 

  44. Yang, L., R. A. Kandel, G. Chang, and J. P. Santerre. Polar surface chemistry of nanofibrous polyurethane scaffold affects annulus fibrosus cell attachment and early matrix accumulation. J. Biomed. Mater. Res. A 91(4):1089–1099, 2009.

    PubMed  Google Scholar 

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Acknowledgments

This work was supported with funding from the National Institutes of Health (R01 EB02425, R01 AR056624), the Penn Center for Musculoskeletal Disorders, and the Human Frontiers in Science Program.

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Authors and Affiliations

  1. McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, 424 Stemmler Hall, 36th Street and Hamilton Walk, Philadelphia, PA, 19104-6081, USA

    Su-Jin Heo, Nandan L. Nerurkar, Brendon M. Baker, Dawn M. Elliott & Robert L. Mauck

  2. Department of Biomedical Engineering, Inje University, Gimhae, Republic of Korea

    Jung-Woog Shin

  3. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Brendon M. Baker, Dawn M. Elliott & Robert L. Mauck

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  1. Su-Jin Heo
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Correspondence to Robert L. Mauck.

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Associate Editor Michael S. Detamore oversaw the review of this article.

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Heo, SJ., Nerurkar, N.L., Baker, B.M. et al. Fiber Stretch and Reorientation Modulates Mesenchymal Stem Cell Morphology and Fibrous Gene Expression on Oriented Nanofibrous Microenvironments. Ann Biomed Eng 39, 2780–2790 (2011). https://doi.org/10.1007/s10439-011-0365-7

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  • DOI: https://doi.org/10.1007/s10439-011-0365-7

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