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The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue

Nature Biotechnology volume 20, pages 1111–1117 (2002)Cite this article

Abstract

Hypoxic-ischemic injury is a prototype for insults characterized by extensive tissue loss. Seeding neural stem cells (NSCs) onto a polymer scaffold that was subsequently implanted into the infarction cavities of mouse brains injured by hypoxia-ischemia allowed us to observe the multiple reciprocal interactions that spontaneously ensue between NSCs and the extensively damaged brain: parenchymal loss was dramatically reduced, an intricate meshwork of many highly arborized neurites of both host- and donor-derived neurons emerged, and some anatomical connections appeared to be reconstituted. The NSC–scaffold complex altered the trajectory and complexity of host cortical neurites. Reciprocally, donor-derived neurons were seemingly capable of directed, target-appropriate neurite outgrowth (extending axons to the opposite hemisphere) without specific external instruction, induction, or genetic manipulation of host brain or donor cells. These “biobridges” appeared to unveil or augment a constitutive reparative response by facilitating a series of reciprocal interactions between NSC and host, including promoting neuronal differentiation, enhancing the elaboration of neural processes, fostering the re-formation of cortical tissue, and promoting connectivity. Inflammation and scarring were also reduced, facilitating reconstitution.

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Figure 1: Formation of a large cavity (arrow) within the necrotic region.
Figure 2: Characterization of NSCs in vitro when seeded upon a PGA scaffold.
Figure 3: Implantation of NSC–PGA complexes into a region of cavity formation following extensive HI brain injury and necrosis.
Figure 4: Characterization in vivo of the neural composition of NSC–PGA complexes within the HI-injured brain.
Figure 5: Long-distance neuronal connections extend from the transplanted NSC–PGA complexes in the HI-injured brain toward presumptive target regions in the intact contralateral hemisphere.
Figure 6: Adverse secondary events that typically follow injury (e.g., monocyte infiltration and astroglial scar formation) are minimized by and within the NSC–PGA complex.

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Acknowledgements

This work was supported in part by grants to K.I.P. from the Stem Cell Research Program of the Korean Ministry of Science and Technology and CMB-Yuhan grant of Yonsei University College of Medicine Research Fund of 1998 and the Basic Research program of the Korean Science and Engineering Foundation, and by grants to E.Y.S. from the March of Dimes, National Institutes of Neurological Diseases & Stroke, and Project ALS. We thank Erin Lavik and Robert Langer for the scanning electron micrograph in Figure 2A.

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Authors and Affiliations

  1. Department of Pediatrics, Pharmacology, and Brain, Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 120-752, Korea

    Kook In Park

  2. Department of Neurology, Harvard Medical School, Boston, 02115, MA, USA

    Kook In Park, Yang D. Teng & Evan Y. Snyder

  3. Department of Neurosurgery, Harvard Medical School, Boston, 02115, MA, USA

    Yang D. Teng

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Correspondence to Evan Y. Snyder.

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Park, K., Teng, Y. & Snyder, E. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat Biotechnol 20, 1111–1117 (2002). https://doi.org/10.1038/nbt751

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