Skip to main content
SpringerLink
Log in

Determining Cell Fate Transition Probabilities to VEGF/Ang 1 Levels: Relating Computational Modeling to Microfluidic Angiogenesis Studies

  • Published:
Cellular and Molecular Bioengineering Aims and scope Submit manuscript

Abstract

Angiogenesis is crucial during many physiological processes, and is influenced by various biochemical and biomechanical factors. Two such factors: VEGF and Ang 1 are known to be critical and we demonstrate here their effect of sprout formation in an in vitro microfluidic system. Previously, we have developed a 3D hybrid, agent-field model where individual cells are modeled as sprout-forming agents in a matrix field. We have conducted microfluidic experiments under different concentrations of VEGF and Ang 1 and analyzed the difference in sprout number and sprout lengths using Decision Tree Analysis. We demonstrate that under specific transition probabilities, the model gives us capillary characteristics similar to those seen in experiments (R 2 ~ 0.82–0.99). Thus, this model can be used to cluster sprout morphology as a function of various influencing factors and, within bounds, predict if a certain growth factor will affect migration or proliferation as it impacts sprout morphology

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Adams, R. H., and K. Alitalo. Molecular regulation of angiogenesis and lymphangiogenesis. Nat. Rev. Mol. Cell Biol. 8:464–478, 2007.

    Article  Google Scholar 

  2. Bogdanovic, E., V. Nguyen, and D. J. Dumont. Activation of Tie2 by angiopoietin-1 and angiopoietin-2 results in their release and receptor internalization. J. Cell Sci. 119:3551–3560, 2006.

    Article  Google Scholar 

  3. Brekken, R. A., and P. E. Thorpe. Vascular endothelial growth factor and vascular targeting of solid tumors. Anticancer Res. 21(6B):4221–4229, 2001.

    Google Scholar 

  4. Cebe Suarez, S., M. Pieren, L. Cariolato, S. Arn, U. Hoffmann, A. Bogucki, C. Manlius, J. Wood, and K. Ballmer-Hofer. A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell. Mol. Life Sci. 63(17):2067–2077, 2006.

    Article  Google Scholar 

  5. Chung, B., L. Flanagan, S. Rhee, P. Schwarz, A. Lee, E. Monuki, and N. Jeon. Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. Lab. Chip. 5(4):401–406, 2005.

    Article  Google Scholar 

  6. Chung, S., R. Sudo, P. J. Mack, C. R. Wan, V. Vickerman, and R. D. Kamm. Cell migration into scaffolds under co-culture conditions in a microfluidic platform. Lab. Chip. 9(2):269–275, 2009.

    Article  Google Scholar 

  7. Das, A., H. Asada, D. Lauffenburger, and R. D. Kamm. A hybrid continuum-discrete modelling approach to predict and control angiogenesis: analysis of combinatorial growth factor and matrix effects on vessel-sprouting morphology. Philos. Trans. A Math. Phys. Eng. Sci. 368(1921):2937–2960, 2010.

    MathSciNet  MATH  Google Scholar 

  8. Davis, S., T. H. Aldrich, P. F. Jones, A. Acheson, D. L. Compton, V. Jain, T. E. Ryan, J. Bruno, C. Radziejewski, P. C. Maisonpierre, and G. D. Yancopoulos. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87(7):1161–1169, 1996.

    Article  Google Scholar 

  9. Folkman, J., and Y. Shing. Angiogenesis. J. Biol. Chem. 267(16):10931–10934, 1992.

    Google Scholar 

  10. Frisk, T., S. Rydholm, T. Liebmann, H. Svahn, G. Stemme, and H. Brismar. A microfluidic device for parallel 3-D cell cultures in asymmetric environments. Electrophoresis 28:4705–4712, 2007.

    Article  Google Scholar 

  11. Garcia-Cardeña, G., J. Comander, K. R. Anderson, B. R. Blackman, and M. A. Gimbrone. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc. Natl Acad. Sci. U.S.A. 98:4478–4485, 2001.

    Article  Google Scholar 

  12. Gavard, J., V. Patel, and J. S. Gutkind. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev. Cell 14:25–36, 2008.

    Article  Google Scholar 

  13. Gengrinovitch, S., S. M. Greenberg, T. Cohen, et al. Platelet factor-4 inhibits the mitogenic activity of VEGF121 and VEGF165 using several concurrent mechanisms. J. Biol. Chem. 270:15059–15065, 1995.

    Article  Google Scholar 

  14. Gomez-Sjoberg, R., A. Leyrat, D. Pirone, C. Chen, and S. Quake. Versatile, fully automated, microfluidic cell culture system. Anal Chem. 79:8557–8563, 2007.

    Article  Google Scholar 

  15. Gu, W., X. Zhu, N. Futai, B. Cho, and S. Takayama. Computerized microfluidic cell culture using elastomeric channels and Braille displays. Proc. Natl Acad. Sci. U.S.A. 101(45):15861–15866, 2004.

    Article  Google Scholar 

  16. Hayes, A. J., W. Q. Huang, J. Mallah, D. Yang, M. E. Lippman, and L. Y. Li. Angiopoietin-1 and its receptor Tie-2 participate in the regulation of capillary-like tubule formation and survival of endothelial cells. Microvasc. Res. 58(3):224–237, 1999.

    Article  Google Scholar 

  17. Helm, C. L., M. E. Fleury, A. H. Zisch, F. Boschetti, and M. A. Swartz. Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism. Proc. Natl Acad. Sci. U.S.A. 102(44):15779–15784, 2005.

    Article  Google Scholar 

  18. Hernández Vera, R., E. Genové, L. Alvarez, S. Borrós, R. Kamm, D. Lauffenburger, and C. E. Semino. Interstitial fluid flow intensity modulates endothelial sprouting in restricted Src-activated cell clusters during capillary morphogenesis. Tissue Eng. Part A 15(1):175–185, 2009.

    Article  Google Scholar 

  19. Hua, F., S. Hautaniemi, R. Yokoo, D. A. Lauffenburger. Integrated mechanistic and data-driven modelling for multivariate analysis of signaling pathways. J. R. Soc. Interface 3(9):515–526, 2006.

    Article  Google Scholar 

  20. Huang, S., and D. Ingber. Shape-dependent control of cell growth, differentiation, apoptosis: switching between attractors in cell regulatory networks. Exp. Cell Res. 261:91–103, 2000.

    Article  Google Scholar 

  21. Jeon, N. L., H. Baskaran, S. K. W. Dertinger, G. M. Whitesides, L. Van De Water, and M. Toner. Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nat. Biotechnol. 20(8):826–830, 2002.

    Google Scholar 

  22. Jones, M. K., M. Tomikawa, B. Mohajer, and A. S. Tarnawski. Gastrointestinal mucosal regeneration: role of growth factors. Front Biosci. 15(4):D303–D309, 1999.

    Google Scholar 

  23. Jośko, J., B. Gwóźdź, H. Jedrzejowska-Szypułka, and S. Hendryk. Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. Med. Sci. Monit. 6(5):1047–1052, 2000.

    Google Scholar 

  24. Koblizek, T. I., C. Weiss, G. D. Yancopoulos, U. Deutsch, and W. Risau. Angiopoietin-1 induces sprouting angiogenesis in vitro. Curr. Biol. 8(9):529–532, 1998.

    Article  Google Scholar 

  25. Kothapalli, C. R., S. de Valence, J. E. Van Veen, S. Chung, F. B. Gertler, and R. D. Kamm. A high-throughput microfluidic assay to study axonal response to growth factor gradients. Lab. Chip. (in review).

  26. Kwak, H. J., J. N. So, S. J. Lee, I. Kim, and G. Y. Koh. Angiopoietin-1 is an apoptosis survival factor for endothelial cells. FEBS Lett. 448(2–3):249–253, 1999.

    Article  Google Scholar 

  27. Li, X., M. Stankovic, C. S. Bonder, et al. Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1. Blood 111:3489–3497, 2008.

    Article  Google Scholar 

  28. Maione, T. E., G. S. Gray, and J. Petro. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science 247:77–79, 1990.

    Article  Google Scholar 

  29. Nakatsu, M., C. A. R. Sainson, J. N. Aoto, K. L. Taylor, M. Aitkenhead, S. Pérez-del-Pulgar, P. M. Carpenter, and C. C. W. Hughesa. Angiogenic sprouting and capillary lumen formation modeled by human umbilical vein endothelial cells (HUVEC) in fibrin gels: the role of fibroblasts and Angiopoietin-1. Microvasc. Res. 66:102–112, 2003.

    Article  Google Scholar 

  30. Saadi, W., S. Rhee, F. Lin, B. Vahidi, B. Chung, and N. Jeon. Generation of stable concentration gradients in 2D and 3D environments using a microfluidic ladder chamber. Biomed. Microdevices 9(5):627–635, 2007.

    Article  Google Scholar 

  31. Slungaard, A. Platelet factor 4: a chemokine enigma. Int. J. Biochem. Cell Biol. 37(6):1162–1167, 2005.

    Article  Google Scholar 

  32. Sudo, R., S. Chung, I. K. Zervantonakis, V. Vickerman, Y. Toshimitsu, L. G. Griffith, and R. D. Kamm. Transport-mediated angiogenesis in 3D epithelial coculture. FASEB J. 23(7):2155–2164, 2009.

    Article  Google Scholar 

  33. Teichert-Kuliszewska, K., P. C. Maisonpierre, N. Jones, A. I. Campbell, Z. Master, M. P. Bendeck, K. Alitalo, D. J. Dumont, G. D. Yancopoulos, and D. J. Stewart. Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of Tie2. Cardiovasc. Res. 49(3):659–670, 2001.

    Article  Google Scholar 

  34. Thomas, M., and H. G. Augustin. The role of the Angiopoietins in vascular morphogenesis. Angiogenesis 12(2):125–37, 2009. Epub 2009 May 16.

    Google Scholar 

  35. Tourovskaia, A., X. Figueroa-Masot, and A. Folch. Differentiation-on-a-chip: a microfluidic platform for long-term cell culture studies. Lab Chip. 5(1):14–19, 2005.

    Article  Google Scholar 

  36. Vickerman, V., J. Blundo, S. Chung, and R. Kamm. Design, fabrication and implementation of a novel multi-parameter control microfluidic platform for three-dimensional cell culture and real-time imaging. Lab. Chip. 8(9):1468–1477, 2008.

    Article  Google Scholar 

  37. von Hundelshausen, P., F. Petersen, and E. Brandt. Platelet-derived chemokines in vascular biology. Thromb. Haemost. 97:704–713, 2007.

    Google Scholar 

  38. Witzenbichler, B., P. C. Maisonpierre, P. Jones, G. D. Yancopoulos, and J. M. Isner. Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2. J. Biol. Chem. 273(29):18514–18521, 1998.

    Article  Google Scholar 

  39. Yamamura, N., R. Sudo, M. Ikeda, and K. Tanishita. Effects of the mechanical properties of collagen gel on the in vitro formation of microvessel networks by endothelial cells. Tissue Eng. 13(7):1443–1453, 2007.

    Article  Google Scholar 

  40. Zhu, W. H., A. MacIntyre, and R. F. Nicosia. Regulation of angiogenesis by vascular endothelial growth factor and angiopoietin-1 in the rat aorta model: distinct temporal patterns of intracellular signaling correlate with induction of angiogenic sprouting. Am. J. Pathol. 161(3):823–830, 2002.

    Google Scholar 

Download references

Acknowledgments

We would like to thank Wahleed Farhat for designing the microfluidic device wafers. We would like to acknowledge NSF-EFRI grant# 0735997 and the Singapore-MIT Alliance for Research and Technology for funding.

Author information

Authors and Affiliations

  1. Departments of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Anusuya Das, Doug Lauffenburger & Roger Kamm

  2. Departments of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Harry Asada & Roger Kamm

  3. Departments of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Room NE47-319, Cambridge, MA, 02139, USA

    Anusuya Das

Authors
  1. Anusuya Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Doug Lauffenburger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Harry Asada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roger Kamm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anusuya Das.

Additional information

Associate Editor David Odde oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Well developed sprouts were observed under conditions with relatively high concentration of Ang 1. The sprouts obtained were tubular with fewer active cells (Fig. 1). Poorly developed sprouts were obtained when the vEGF concentrations were high, but Ang 1 concentrations were low. They were not tubular and had many active cells along the sprouts. (Fig. 2)

Supplementary material 1 (DOC 762 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Das, A., Lauffenburger, D., Asada, H. et al. Determining Cell Fate Transition Probabilities to VEGF/Ang 1 Levels: Relating Computational Modeling to Microfluidic Angiogenesis Studies. Cel. Mol. Bioeng. 3, 345–360 (2010). https://doi.org/10.1007/s12195-010-0146-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12195-010-0146-7

Keywords

Search

Navigation