Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Transplantation of brain cells assembled around a programmable synthetic microenvironment

Abstract

Cell therapy is a promising method for treatment of hematopoietic disorders, neurodegenerative diseases, diabetes, and tissue loss due to trauma. Some of the major barriers to cell therapy have been partially addressed, including identification of cell populations, in vitro cell proliferation, and strategies for immunosuppression. An unsolved problem is recapitulation of the unique combinations of matrix, growth factor, and cell adhesion cues that distinguish each stem cell microenvironment, and that are critically important for control of progenitor cell differentiation and histogenesis. Here we describe an approach in which cells, synthetic matrix elements, and controlled-release technology are assembled and programmed, before transplantation, to mimic the chemical and physical microenvironment of developing tissue. We demonstrate this approach in animals using a transplantation system that allows control of fetal brain cell survival and differentiation by pre-assembly of neo-tissues containing cells and nerve growth factor (NGF)-releasing synthetic particles.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Formation of neo-tissues.
Figure 2: Microparticle and synthetic microenvironment characterization.
Figure 3: NGF-enriched synthetic microenvironment-induced biological activity.
Figure 4: Predicted distribution of NGF in neo-tissues containing NGF-releasing microparticles.

Similar content being viewed by others

References

  1. Watt, F.M. & Hogan, B.L.M. Out of eden: stem cells and their niches. Science. 287, 1427–1430 (2000).

    Article  CAS  Google Scholar 

  2. Freed, C.R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med. 8, 710–719 (2001).

    Article  Google Scholar 

  3. Freed, C.R. et al. Survival of implanted fetal dopamine cells and neurological improvement 12 to 46 months after transplantation. N. Engl. J. of Med. 327, 1549 (1992).

    Article  CAS  Google Scholar 

  4. Spencer, D.D. et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease. N. Engl. J. Med. 327, 1541–1548 (1992).

    Article  CAS  Google Scholar 

  5. Kordower, J.H. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N. Engl. J. Med. 332, 1118 (1995).

    Article  CAS  Google Scholar 

  6. Philpott, L.M. et al. Neuropsychological functioning following fetal striatal transplantation in Huntington's chorea: three case presentations. Cell Transplant. 6, 203–212 (1997).

    Article  CAS  Google Scholar 

  7. Fink, J.S. et al. Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results. Cell Transplant. 9, 273–278 (2000).

    Article  CAS  Google Scholar 

  8. Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    Article  CAS  Google Scholar 

  9. McDonald, J.W. et al. Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat. Med. 5, 1410–1412 (1999).

    Article  CAS  Google Scholar 

  10. Gage, F.H. et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci. USA 92, 11879–11883 (1995).

    Article  CAS  Google Scholar 

  11. Snyder, E.Y., Yoon, C., Flax, J.D. & Macklis, J.D. Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc. Natl. Acad. Sci. USA 94, 11663–11668 (1997).

    Article  CAS  Google Scholar 

  12. Isacson, O. & Deacon, T. Neural transplantation studies reveal the brain's capacity for continuous reconstruction. Trends Neurosci. 20, 477–482 (1997).

    Article  CAS  Google Scholar 

  13. Mezey, E., Chandross, K.J., Harta, G., Maki, R.A. & McKercher, S.R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290, 1672–1674 (2000).

    Article  Google Scholar 

  14. Brazelton, T.R., Rossi, F.M., Keshet, G.L. & Blau, H.M. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290, 1672–1674 (2000).

    Article  Google Scholar 

  15. Azizi, S.A., Stokes, D., Augelli, B.J., DiGirolamo, C. & Prockop, D.J. Engraftment and migration of human bone marrow stromal cells in the brains of albino rats—similarity to astrocyte grafts. Proc. Natl. Acad. Sci. USA 95, 3908 (1998).

  16. McKerracher, L. et al. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811 (1994).

    Article  CAS  Google Scholar 

  17. Caroni, P. & Schwab, M.E. Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85–96 (1988).

    Article  CAS  Google Scholar 

  18. McKeon, R.J., Schreiber, R.C., Rudge, J.S. & Silver, J. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J. Neurosci. 11, 3398–3411 (1991).

    Article  CAS  Google Scholar 

  19. Davies, S.J.A. et al. Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390, 680–683 (1997).

    Article  CAS  Google Scholar 

  20. Horner, P.J. & Gage, F.H. Regenerating the damaged central nervous system. Nature 407, 963–970 (2000).

    Article  CAS  Google Scholar 

  21. Huang, D.W., McKerracher, L., Braun, P.E. & David, S. A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord. Neuron 24, 639–647 (1999).

    Article  CAS  Google Scholar 

  22. Bregman, B.S. et al. Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501 (1995).

    Article  CAS  Google Scholar 

  23. Schnell, L. & Schwab, M.E. Axonal regeneration in the rat spinal cord produced by an antibody against myelin-associated neurite growth inhibitors. Nature 343, 269–272 (1990).

    Article  CAS  Google Scholar 

  24. Cai, D., Shen, Y., Bellard, M.D., Tang, S. & Filbin, M.T. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101 (1999).

    Article  CAS  Google Scholar 

  25. Dekker, A. & Thal, L. Nerve growth factor increases cortical choline acetyltransferase-positive fiber staining without affecting cortical cholinergic neurons. Brain Res. 601, 329–332 (1993).

    Article  CAS  Google Scholar 

  26. Kordower, J.H. et al. The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor. Proc. Natl. Acad. Sci. USA 91, 10898–10902 (1994).

    Article  CAS  Google Scholar 

  27. McAllister, A.K., Katz, L.C. & Lo, D.C. Neurotrophins and synaptic plasticity. Annu. Rev. Neurosci. 22, 295–318 (1999).

    Article  CAS  Google Scholar 

  28. Sherwood, N., Lesser, S. & Lo, D. Neurotrophin regulation of ionic currents and cell size depends on cell context. Proc. Natl. Acad. Sci. USA 94, 5917–5922 (1997).

    Article  CAS  Google Scholar 

  29. Kruttgen, A., Moller, J., Heymach, J. & Shooter, E. Neurotrophins induce release of neurotrophins by the regulated secretory pathway. Proc. Natl. Acad. Sci. USA 95, 9614–9619 (1998).

    Article  CAS  Google Scholar 

  30. Lambiase, A., Rama, P., Bonini, S., Caprioglio, G. & Aloe, L. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N. Engl. J. Med. 338, 1174–1180 (1998).

    Article  CAS  Google Scholar 

  31. Lewin, G.R. & Mendell, L.M. Nerve growth factor and nociception. Trends Neurosci. 16, 353–359 (1993).

    Article  CAS  Google Scholar 

  32. Petty, B.G. et al. The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann. Neurol. 36, 244–246 (1994).

    Article  CAS  Google Scholar 

  33. Williams, L.R. Hypophagia is induced by intracerebroventricular administration of nerve growth factor. Exp. Neurol. 113, 31–37 (1991).

    Article  CAS  Google Scholar 

  34. Hatanaka, H. & Tsukui, H. Differential effects of nerve-growth factor and glioma-conditioned medium on neurons cultured from various regions of fetal rat central nervous system. Dev. Brain Res. 30, 47–56 (1986).

    Article  CAS  Google Scholar 

  35. Garofalo, L. & Cuello, A.C. Pharmacological characterization of nerve growth factor and/or monosialoganglioside GM1 effects on cholinergic markers in the adult lesioned brain. J. Pharmacol. Exp. Ther. 272, 527–545 (1995).

    CAS  PubMed  Google Scholar 

  36. Mahoney, M.J. Cell assembly and growth factor delivery: factors enhancing the function of transplanted nervous tissue. PhD Thesis, Cornell University (2000).

  37. Moscona, A.A. Rotation-mediated histogenic aggregation of dissociated cells. A quantifiable approach to cell interactions in vitro. Exp. Cell Res. 22, 455–475 (1961).

    Article  CAS  Google Scholar 

  38. Yavin, Z. & Yavin, E. Attachment and culture of dissociated cells from rat cerebral hemispheres on poly-lysine-coated surface. J. Cell Biol. 62, 540–546 (1974).

    Article  CAS  Google Scholar 

  39. Miyatani, S. et al. Neural cadherin: role in selective cell–cell adhesion. Science 245, 631–635 (1989).

    Article  CAS  Google Scholar 

  40. Alberts, B. et al. Molecular and cellular biology of the cell. (Garland Publishing, New York, NY; 1994).

    Google Scholar 

  41. Hutton, L. & Perez-Polo, J. In vitro glial responses to nerve growth factor. J. Neurosci. Res. 41, 185–196 (1995).

    Article  CAS  Google Scholar 

  42. Dai, W., Belt, J. & Saltzman, W.M. Cell-binding peptides conjugated to poly(ethylene glycol) promote neural cell aggregation. Bio/Technology. 12, 797–801 (1994).

    CAS  PubMed  Google Scholar 

  43. Mahoney, M. & Saltzman, W.M. Controlled release of proteins to tissue transplants for the treatment of neurodegenerative disorders. J. Pharm. Sci. 85, 1276–1281 (1996).

    Article  CAS  Google Scholar 

  44. Hong, K., Nishiyama, M., Henley, J., Tessier-Lavigne, M. & Poo, M. Calcium signalling in the guidance of nerve growth by netrin-1. Nature 403, 93–98 (2000).

    Article  CAS  Google Scholar 

  45. Song, H., Ming, G. & Poo, M. cAMP-induced switching in turning direction of nerve growth cones. Nature 388, 275–279 (1997).

    Article  CAS  Google Scholar 

  46. Krewson, C.E. & Saltzman, W.M. Distribution of nerve growth factor following direct delivery to the brain interstitium. Brain Res. 680, 196 (1995).

    Article  CAS  Google Scholar 

  47. Nonner, D., Brass, B.J., Barrett, E.F. & Barrett, J.N. Reversibility of nerve growth factor's enhancement of choline acetyltransferase activity in cultured embryonic rat septum. Exp. Neurol. 122, 196–208 (1993).

    Article  CAS  Google Scholar 

  48. Luo, D., Woodrow-Mumford, K., Belcheva, N. & Saltzman, W.M. Controlled DNA delivery systems. Pharm. Res. 16, 1299–1307 (1999).

    Article  Google Scholar 

  49. Beaty, C.E. & Saltzman, W.M. Controlled growth factor delivery induces differential neurite outgrowth in three-dimensional cell cultures. J. Controlled Release 24, 15–23 (1993).

    Article  CAS  Google Scholar 

  50. Mahoney, M. & Saltzman, W.M. Cultures of cells from fetal rat brain: methods to control composition, morphology, and biochemical activity. Biotechnol. Bioeng. 62, 461–467 (1999).

    Article  CAS  Google Scholar 

  51. Mahoney, M. & Saltzman, W.M. Millimeter-scale positioning of a nerve-growth factor source and biological activity in the brain. Proc. Natl. Acad. Sci. USA 96, 4536–4539 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Aeronautics and Space Administration (NASA) Grant NAG 8-1372 and National Institutes of Health Grant NS-038470. M.J.M. was supported by a grant from the NASA Graduate Student Research Program.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W. Mark Saltzman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mahoney, M., Saltzman, W. Transplantation of brain cells assembled around a programmable synthetic microenvironment. Nat Biotechnol 19, 934–939 (2001). https://doi.org/10.1038/nbt1001-934

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt1001-934

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing