Skip to main content

Advertisement

SpringerLink
Log in

Endothelial Cells Exposed to Fluid Shear Stress Support Diffusion Based Maturation of Adult Neural Progenitor Cells

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

Abstract

Introduction

The neural stem cell (NSC) niche is a highly complex cellular and biochemical milieu supporting proliferating NSCs and neural progenitor cells (NPCs) with close apposition to the vasculature, primarily comprised of endothelial cells (ECs). Current in vitro models of the niche incorporate EC-derived factors, but do not reflect the physiologically relevant hemodynamic state of the ECs or the spatial resolution observed between cells within the niche.

Methods

In this work, we developed a novel in vitro model of the niche that (1) incorporates ECs cultured with fluid shear stress and (2) fosters paracrine cytokine gradients between ECs and NSCs in a spatiotemporal configuration mimicking the cytoarchitecture of the subventricular niche. A modified cone and plate viscometer was used to generate a shear stress of 10 dynes cm−2 for ECs cultured on a membrane, while statically cultured NPCs are 10 or 1000 μm below the ECs.

Results

NPCs cultured within 10 μm of dynamic ECs exhibit increased PSA-NCAM+ and OLIG2+ cells compared to progenitors in all other culture regimes and the hemodynamic EC phenotype results in distinct progeny phenotypes. This co-culture regime yields greater release of pro-neurogenic factors, suggesting a potential mechanism for the observed progenitor maturation.

Conclusions

Based on these results, models incorporating ECs exposed to shear stress allow for paracrine signaling gradients and regulate NPC lineage progression with appropriate niche spatial resolution occurring at 10 μm. This model could be used to evaluate cellular or pharmacological interactions within the healthy, diseased, or aged brain.

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

Similar content being viewed by others

References

  1. Ahn, S. M., K. Byun, D. Kim, K. Lee, J. S. Yoo, S. U. Kim, et al. Olig2-induced neural stem cell differentiation involves downregulation of Wnt signaling and induction of Dickkopf-1 expression. PLoS ONE. 3:e3917, 2008.

    Article  Google Scholar 

  2. Ando, J., and K. Yamamoto. Vascular mechanobiology: endothelial cell responses to fluid shear stress. Circ. J. 73:1983–1992, 2009.

    Article  Google Scholar 

  3. Arisaka, T., M. Mitsumata, M. Kawasumi, T. Tohjima, S. Hirose, and Y. Yoshida. Effects of shear stress on glycosaminoglycan synthesis in vascular endothelial cells. Ann. N Y Acad. Sci. 748:543–554, 1995.

    Article  Google Scholar 

  4. Aviezer, D., E. Levy, M. Safran, C. Svahn, E. Buddecke, A. Schmidt, et al. Differential structural requirements of heparin and heparan sulfate proteoglycans that promote binding of basic fibroblast growth factor to its receptor. J. Biol. Chem. 269:114–121, 1994.

    Google Scholar 

  5. Bandtlow, C. E., and D. R. Zimmermann. Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol. Rev. 80:1267–1290, 2000.

    Article  Google Scholar 

  6. Barakat, A., and D. Lieu. Differential responsiveness of vascular endothelial cells to different types of fluid mechanical shear stress. Cell Biochem. Biophys. 38:323–343, 2003.

    Article  Google Scholar 

  7. Capela, A., and S. Temple. LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron. 35:865–875, 2002.

    Article  Google Scholar 

  8. Chang, Z., K. Meyer, A. C. Rapraeger, and A. Friedl. Differential ability of heparan sulfate proteoglycans to assemble the fibroblast growth factor receptor complex in situ. FASEB J. 14:137–144, 2000.

    Article  Google Scholar 

  9. Chiu, J. J., L. J. Chen, C. N. Chen, P. L. Lee, and C. I. Lee. A model for studying the effect of shear stress on interactions between vascular endothelial cells and smooth muscle cells. J. Biomech. 37:531–539, 2004.

    Article  Google Scholar 

  10. Davies, P. F. Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75:519–560, 1995.

    Article  Google Scholar 

  11. Delgado, A. C., S. R. Ferron, D. Vicente, E. Porlan, A. Perez-Villalba, C. M. Trujillo, et al. Endothelial NT-3 delivered by vasculature and CSF promotes quiescence of subependymal neural stem cells through nitric oxide induction. Neuron. 83:572–585, 2014.

    Article  Google Scholar 

  12. Ding, B. S., D. J. Nolan, J. M. Butler, D. James, A. O. Babazadeh, Z. Rosenwaks, et al. Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature. 468:310–315, 2010.

    Article  Google Scholar 

  13. Doetsch, F. A niche for adult neural stem cells. Curr. Opin. Genet. Dev. 13:543–550, 2003.

    Article  Google Scholar 

  14. Donnelly, D. J., and P. G. Popovich. Inflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury. Exp. Neurol. 209:378–388, 2008.

    Article  Google Scholar 

  15. Douet, V., A. Kerever, E. Arikawa-Hirasawa, and F. Mercier. Fractone-heparan sulphates mediate FGF-2 stimulation of cell proliferation in the adult subventricular zone. Cell Prolif. 46:137–145, 2013.

    Article  Google Scholar 

  16. Dumont, C. M., J. M. Piselli, N. Kazi, E. Bowman, G. Li, R. J. Linhardt, et al. Factors released from endothelial cells exposed to flow impact adhesion, proliferation, and fate choice in the adult neural stem cell lineage. Stem Cells Dev. 26:1–15, 2017.

    Article  Google Scholar 

  17. Falk, A., and J. Frisen. Amphiregulin is a mitogen for adult neural stem cells. J. Neurosci. Res. 69:757–762, 2002.

    Article  Google Scholar 

  18. Fernandez-Martos, C. M., C. Gonzalez-Fernandez, P. Gonzalez, A. Maqueda, E. Arenas, and F. J. Rodriguez. Differential expression of Wnts after spinal cord contusion injury in adult rats. PLoS ONE. 6:e27000, 2011.

    Article  Google Scholar 

  19. Gama Sosa, M. A., R. De Gasperi, A. B. Rocher, G. M. Perez, K. Simons, D. E. Cruz, et al. Interactions of primary neuroepithelial progenitor and brain endothelial cells: distinct effect on neural progenitor maintenance and differentiation by soluble factors and direct contact. Cell Res. 17:619–626, 2007.

    Article  Google Scholar 

  20. Gomez-Nicola, D., B. Valle-Argos, N. Pallas-Bazarra, and M. Nieto-Sampedro. Interleukin-15 regulates proliferation and self-renewal of adult neural stem cells. Mol. Biol. Cell. 22:1960–1970, 2011.

    Article  Google Scholar 

  21. Gomez-Nicola, D., B. Valle-Argos, M. Suardiaz, J. S. Taylor, and M. Nieto-Sampedro. Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: regulation of macrophage and T-cell infiltration. J. Neurochem. 107:1741–1752, 2008.

    Article  Google Scholar 

  22. Gonzalez-Perez, O., F. Gutierrez-Fernandez, V. Lopez-Virgen, J. Collas-Aguilar, A. Quinones-Hinojosa, and J. M. Garcia-Verdugo. Immunological regulation of neurogenic niches in the adult brain. Neuroscience. 226:270–281, 2012.

    Article  Google Scholar 

  23. Gordon, R. J., N. F. Mehrabi, C. Maucksch, and B. Connor. Chemokines influence the migration and fate of neural precursor cells from the young adult and middle-aged rat subventricular zone. Exp. Neurol. 233:587–594, 2012.

    Article  Google Scholar 

  24. Gritli-Linde, A., P. Lewis, A. P. McMahon, and A. Linde. The whereabouts of a morphogen: direct evidence for short- and graded long-range activity of hedgehog signaling peptides. Dev. Biol. 236:364–386, 2001.

    Article  Google Scholar 

  25. Gruber, R. C., A. K. Ray, C. T. Johndrow, H. Guzik, D. Burek, P. G. de Frutos, et al. Targeted GAS6 delivery to the CNS protects axons from damage during experimental autoimmune encephalomyelitis. J. Neurosci. 34:16320–16335, 2014.

    Article  Google Scholar 

  26. Hagihara, K., K. Watanabe, J. Chun, and Y. Yamaguchi. Glypican-4 is an FGF2-binding heparan sulfate proteoglycan expressed in neural precursor cells. Dev. Dyn. 219:353–367, 2000.

    Article  Google Scholar 

  27. Han, J., F. Zhang, J. Xie, R. J. Linhardt, and L. M. Hiebert. Changes in cultured endothelial cell glycosaminoglycans under hyperglycemic conditions and the effect of insulin and heparin. Cardiovasc. Diabetol. 8:46, 2009.

    Article  Google Scholar 

  28. Hastings, N. E., M. B. Simmers, O. G. McDonald, B. R. Wamhoff, and B. R. Blackman. Atherosclerosis-prone hemodynamics differentially regulates endothelial and smooth muscle cell phenotypes and promotes pro-inflammatory priming. Am. J. Physiol. Cell. Physiol. 293:C1824–C1833, 2007.

    Article  Google Scholar 

  29. Heydarkhan-Hagvall, S., S. Chien, S. Nelander, Y. C. Li, S. Yuan, J. Lao, et al. DNA microarray study on gene expression profiles in co-cultured endothelial and smooth muscle cells in response to 4- and 24-h shear stress. Mol. Cell. Biochem. 281:1–15, 2006.

    Article  Google Scholar 

  30. Hui, E. E., and S. N. Bhatia. Micromechanical control of cell-cell interactions. Proc. Natl. Acad. Sci. USA. 104:5722–5726, 2007.

    Article  Google Scholar 

  31. Ida, M., T. Shuo, K. Hirano, Y. Tokita, K. Nakanishi, F. Matsui, et al. Identification and functions of chondroitin sulfate in the milieu of neural stem cells. J. Biol. Chem. 281:5982–5991, 2006.

    Article  Google Scholar 

  32. Kato, T., H. Sasaki, T. Katagiri, H. Sasaki, K. Koiwai, H. Youki, et al. The binding of basic fibroblast growth factor to Alzheimer’s neurofibrillary tangles and senile plaques. Neurosci. Lett. 122:33–36, 1991.

    Article  Google Scholar 

  33. Kerever, A., J. Schnack, D. Vellinga, N. Ichikawa, C. Moon, E. Arikawa-Hirasawa, et al. Novel extracellular matrix structures in the neural stem cell niche capture the neurogenic factor fibroblast growth factor 2 from the extracellular milieu. Stem Cells. 25:2146–2157, 2007.

    Article  Google Scholar 

  34. Knerlich-Lukoschus, F., B. von der Ropp-Brenner, R. Lucius, H. M. Mehdorn, and J. Held-Feindt. Spatiotemporal CCR1, CCL3(MIP-1alpha), CXCR4, CXCL12(SDF-1alpha) expression patterns in a rat spinal cord injury model of posttraumatic neuropathic pain. J. Neurosurg. Spine. 14:583–597, 2011.

    Article  Google Scholar 

  35. Kokovay, E., S. Goderie, Y. Wang, S. Lotz, G. Lin, Y. Sun, et al. Adult SVZ lineage cells home to and leave the vascular niche via differential responses to SDF1/CXCR4 signaling. Cell Stem Cell. 7:163–173, 2010.

    Article  Google Scholar 

  36. Kuzumaki, N., D. Ikegami, S. Imai, M. Narita, R. Tamura, M. Yajima, et al. Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice. Synapse. 64:721–728, 2010.

    Article  Google Scholar 

  37. LaMack, J. A., and M. H. Friedman. Individual and combined effects of shear stress magnitude and spatial gradient on endothelial cell gene expression. Am. J. Physiol. Heart Circ. Physiol. 293:H2853–H2859, 2007.

    Article  Google Scholar 

  38. Lapidot, T., A. Dar, and O. Kollet. How do stem cells find their way home? Blood. 106:1901–1910, 2005.

    Article  Google Scholar 

  39. Lehtinen, M. K., M. W. Zappaterra, X. Chen, Y. J. Yang, A. D. Hill, M. Lun, et al. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron. 69:893–905, 2011.

    Article  Google Scholar 

  40. Li, Q., M. C. Ford, E. B. Lavik, and J. A. Madri. Modeling the neurovascular niche: VEGF- and BDNF-mediated cross-talk between neural stem cells and endothelial cells: an in vitro study. J. Neurosci. Res. 84:1656–1668, 2006.

    Article  Google Scholar 

  41. Lipowsky, H. H. Microvascular rheology and hemodynamics. Microcirculation. 12:5–15, 2005.

    Article  Google Scholar 

  42. Lowry, N., S. K. Goderie, M. Adamo, P. Lederman, C. Charniga, J. Gill, et al. Multipotent embryonic spinal cord stem cells expanded by endothelial factors and Shh/RA promote functional recovery after spinal cord injury. Exp. Neurol. 209:510–522, 2008.

    Article  Google Scholar 

  43. Morita, T., M. Yoshizumi, H. Kurihara, K. Maemura, R. Nagai, and Y. Yazaki. Shear stress increases heparin-binding epidermal growth factor-like growth factor mRNA levels in human vascular endothelial cells. Biochem. Biophys. Res. Commun. 197:256–262, 1993.

    Article  Google Scholar 

  44. Nikolova, G., B. Strilic, and E. Lammert. The vascular niche and its basement membrane. Trends Cell Biol. 17:19–25, 2007.

    Article  Google Scholar 

  45. Nugent, M. A., and E. R. Edelman. Kinetics of basic fibroblast growth factor binding to its receptor and heparan sulfate proteoglycan: a mechanism for cooperactivity. Biochemistry. 31:8876–8883, 1992.

    Article  Google Scholar 

  46. Ottone, C., B. Krusche, A. Whitby, M. Clements, G. Quadrato, M. E. Pitulescu, et al. Direct cell-cell contact with the vascular niche maintains quiescent neural stem cells. Nat. Cell Biol. 16:1045–1056, 2014.

    Article  Google Scholar 

  47. Ousman, S. S., and S. David. MIP-1alpha, MCP-1, GM-CSF, and TNF-alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J. Neurosci. 21:4649–4656, 2001.

    Google Scholar 

  48. Palma, V., D. A. Lim, N. Dahmane, P. Sanchez, T. C. Brionne, C. D. Herzberg, et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development. 132:335–344, 2005.

    Article  Google Scholar 

  49. Passerini, A. G., A. Milsted, and S. E. Rittgers. Shear stress magnitude and directionality modulate growth factor gene expression in preconditioned vascular endothelial cells. J. Vasc. Surg. 37:182–190, 2003.

    Article  Google Scholar 

  50. Pastrana, E., L. C. Cheng, and F. Doetsch. Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny. Proc. Natl. Acad. Sci. USA. 106:6387–6392, 2009.

    Article  Google Scholar 

  51. Puglianiello, A., D. Germani, P. Rossi, and S. Cianfarani. IGF-I stimulates chemotaxis of human neuroblasts. Involvement of type 1 IGF receptor, IGF binding proteins, phosphatidylinositol-3 kinase pathway and plasmin system. J. Endocrinol. 165:123–131, 2000.

    Article  Google Scholar 

  52. Reisig, K., and A. M. Clyne. Fibroblast growth factor-2 binding to the endothelial basement membrane peaks at a physiologically relevant shear stress. Matrix Biol. 29:586–593, 2010.

    Article  Google Scholar 

  53. Reneman, R. S., and A. P. Hoeks. Wall shear stress as measured in vivo: consequences for the design of the arterial system. Med. Biol. Eng. Comput. 46:499–507, 2008.

    Article  Google Scholar 

  54. Saksela, O., D. Moscatelli, A. Sommer, and D. B. Rifkin. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation. J. Cell Biol. 107:743–751, 1988.

    Article  Google Scholar 

  55. Santaguida, S., D. Janigro, M. Hossain, E. Oby, E. Rapp, and L. Cucullo. Side by side comparison between dynamic versus static models of blood-brain barrier in vitro: a permeability study. Brain Res. 1109:1–13, 2006.

    Article  Google Scholar 

  56. Shen, Q., S. K. Goderie, L. Jin, N. Karanth, Y. Sun, N. Abramova, et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science. 304:1338–1340, 2004.

    Article  Google Scholar 

  57. Shen, Q., Y. Wang, E. Kokovay, G. Lin, S. M. Chuang, S. K. Goderie, et al. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell. 3:289–300, 2008.

    Article  Google Scholar 

  58. Shi, B., J. Ding, Y. Liu, X. Zhuang, X. Zhuang, X. Chen, et al. ERK1/2 pathway-mediated differentiation of IGF-1-transfected spinal cord-derived neural stem cells into oligodendrocytes. PLoS ONE. 9:e106038, 2014.

    Article  Google Scholar 

  59. Sirko, S., A. von Holst, A. Wizenmann, M. Gotz, and A. Faissner. Chondroitin sulfate glycosaminoglycans control proliferation, radial glia cell differentiation and neurogenesis in neural stem/progenitor cells. Development. 134:2727–2738, 2007.

    Article  Google Scholar 

  60. Stepp, D. W., Y. Nishikawa, and W. M. Chilian. Regulation of shear stress in the canine coronary microcirculation. Circulation. 100:1555–1561, 1999.

    Article  Google Scholar 

  61. Sun, L., S. Liu, Q. Sun, Z. Li, F. Xu, C. Hou, et al. Inhibition of TROY promotes OPC differentiation and increases therapeutic efficacy of OPC graft for spinal cord injury. Stem Cells Dev. 23:2104–2118, 2014.

    Article  Google Scholar 

  62. Suzuki, Y., M. Yanagisawa, H. Yagi, Y. Nakatani, and R. K. Yu. Involvement of beta1-integrin up-regulation in basic fibroblast growth factor- and epidermal growth factor-induced proliferation of mouse neuroepithelial cells. J. Biol. Chem. 285:18443–18451, 2010.

    Article  Google Scholar 

  63. Tavazoie, M., L. Van der Veken, V. Silva-Vargas, M. Louissaint, L. Colonna, B. Zaidi, et al. A specialized vascular niche for adult neural stem cells. Cell Stem Cell. 3:279–288, 2008.

    Article  Google Scholar 

  64. Tham, M., S. Ramasamy, H. T. Gan, A. Ramachandran, A. Poonepalli, Y. H. Yu, et al. CSPG is a secreted factor that stimulates neural stem cell survival possibly by enhanced EGFR signaling. PLoS ONE. 5:e15341, 2010.

    Article  Google Scholar 

  65. Thomas, J. A., R. A. Deaton, N. E. Hastings, Y. Shang, C. W. Moehle, U. Eriksson, et al. PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns. Am. J. Physiol. Heart Circ. Physiol. 296:H442–H452, 2009.

    Article  Google Scholar 

  66. Wu, S. M., K. S. Tan, H. Chen, T. T. Beh, H. C. Yeo, S. K. Ng, et al. Enhanced production of neuroprogenitors, dopaminergic neurons, and identification of target genes by overexpression of sonic hedgehog in human embryonic stem cells. Stem Cells Dev. 21:729–741, 2012.

    Article  Google Scholar 

  67. Zhang, J., and Y. De Koninck. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J. Neurochem. 97:772–783, 2006.

    Article  Google Scholar 

  68. Zhang, X., L. Zhang, X. Cheng, Y. Guo, X. Sun, G. Chen, et al. IGF-1 promotes Brn-4 expression and neuronal differentiation of neural stem cells via the PI3 K/Akt pathway. PLoS ONE. 9:e113801, 2014.

    Article  Google Scholar 

Download references

Acknowledgments

The authors acknowledge both the Stem Cell Biology and Microscopy Research Cores within the Center for Biotechnology and Interdisciplinary Studies at Rensselaer Polytechnic Institute. Funding was provided by the National Institutes of Health (RO1AG041861-ST), the National Science Foundation (CBET-1350240 - GD), and the New York State Department of Health NYSTEM (C026419 - DMT).

Conflict of interest

Courtney Dumont, Jennifer Piselli, Sally Temple, Guohao Dai, and Deanna Thompson declare that they have no conflicts of interest.

Ethical Approval

No human studies were carried out by the authors for this article. All animal studies were carried out in accordance with the Institutional Animal Care and Use Committee guidelines at Rensselaer Polytechnic Institute.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA

    C. M. Dumont, J. Piselli, G. Dai & D. M. Thompson

  2. Center for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA

    C. M. Dumont, J. Piselli, G. Dai & D. M. Thompson

  3. Neural Stem Cell Institute, Rensselaer, NY, 12144, USA

    S. Temple

Authors
  1. C. M. Dumont
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Piselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Temple
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. M. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. M. Thompson.

Additional information

Associate Editor Michael R. King oversaw the review of this article.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dumont, C.M., Piselli, J., Temple, S. et al. Endothelial Cells Exposed to Fluid Shear Stress Support Diffusion Based Maturation of Adult Neural Progenitor Cells. Cel. Mol. Bioeng. 11, 117–130 (2018). https://doi.org/10.1007/s12195-017-0516-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12195-017-0516-5

Keywords

Search

Navigation