Journal article
Axonal Tract Reconstruction Using a Tissue-Engineered Nigrostriatal Pathway in a Rat Model of Parkinson’s Disease
International journal of molecular sciences, v 23(22), p13985
12 Nov 2022
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Parkinson’s disease (PD) affects 1–2% of people over 65, causing significant morbidity across a progressive disease course. The classic PD motor deficits are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in the loss of their long-distance axonal projections that modulate striatal output. While contemporary treatments temporarily alleviate symptoms of this disconnection, there is no approach able to replace the nigrostriatal pathway. We applied microtissue engineering techniques to create a living, implantable tissue-engineered nigrostriatal pathway (TE-NSP) that mimics the architecture and function of the native pathway. TE-NSPs comprise a discrete population of dopaminergic neurons extending long, bundled axonal tracts within the lumen of hydrogel micro-columns. Neurons were isolated from the ventral mesencephalon of transgenic rats selectively expressing the green fluorescent protein in dopaminergic neurons with subsequent fluorescent-activated cell sorting to enrich a population to 60% purity. The lumen extracellular matrix and growth factors were varied to optimize cytoarchitecture and neurite length, while immunocytochemistry and fast-scan cyclic voltammetry (FSCV) revealed that TE-NSP axons released dopamine and integrated with striatal neurons in vitro. Finally, TE-NSPs were implanted to span the nigrostriatal pathway in a rat PD model with a unilateral 6-hydroxydopamine SNpc lesion. Immunohistochemistry and FSCV established that transplanted TE-NSPs survived, maintained their axonal tract projections, extended dopaminergic neurites into host tissue, and released dopamine in the striatum. This work showed proof of concept that TE-NSPs can reconstruct the nigrostriatal pathway, providing motivation for future studies evaluating potential functional benefits and long-term durability of this strategy. This pathway reconstruction strategy may ultimately replace lost neuroarchitecture and alleviate the cause of motor symptoms for PD patients.
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- Title
- Axonal Tract Reconstruction Using a Tissue-Engineered Nigrostriatal Pathway in a Rat Model of Parkinson’s Disease
- Creators
- Laura A. Struzyna - University of PennsylvaniaKevin D. Browne - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USAJustin C. Burrell - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USAWisberty J. Gordián Vélez - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USAKathryn L. Wofford - Drexel UniversityHilton M. Kaplan - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USAN. Sanjeeva Murthy - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USAH. Isaac Chen - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USAJohn E. Duda - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USARodrigo A. España - Drexel UniversityD. Kacy Cullen - Center for Brain Injury & Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Center for Neurotrauma, Neurodegeneration & Restoration, Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA 19104, USA Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA New Jersey Center for Biomaterials, Rutgers University, Piscataway, NJ 08854, USA Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA Department of Neurobiology & Anatomy, College of Medicine, Drexel University, Philadelphia, PA 19129, USA
- Publication Details
- International journal of molecular sciences, v 23(22), p13985
- Publisher
- MDPI
- Grant note
- I01-BX003748; I01-BX005079 / Department of Veterans Affairs R01-NS117757; R01-DA031900; T32-NS091006 / National Institutes of Health DGE-1321851 / National Science Foundation 9998 / Michael J. Fox Foundation; Therapeutic Pipeline Program
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000887356800001
- Scopus ID
- 2-s2.0-85142827558
- Other Identifier
- 991019323179004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary