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Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats.

Abstract

Neural precursor cells (NSCs) hold great potential to treat a variety of neurodegenerative diseases and injuries to the spinal cord. However, current delivery techniques require an invasive approach in which an injection needle is advanced into the spinal parenchyma to deliver cells of interest. As such, this approach is associated with an inherent risk of spinal injury, as well as a limited delivery of cells into multiple spinal segments. Here, we characterize the use of a novel cell delivery technique that employs single bolus cell injections into the spinal subpial space. In immunodeficient rats, two subpial injections of human NSCs were performed in the cervical and lumbar spinal cord, respectively. The survival, distribution, and phenotype of transplanted cells were assessed 6-8 months after injection. Immunofluorescence staining and mRNA sequencing analysis demonstrated a near-complete occupation of the spinal cord by injected cells, in which transplanted human NSCs (hNSCs) preferentially acquired glial phenotypes, expressing oligodendrocyte (Olig2, APC) or astrocyte (GFAP) markers. In the outermost layer of the spinal cord, injected hNSCs differentiated into glia limitans-forming astrocytes and expressed human-specific superoxide dismutase and laminin. All animals showed normal neurological function for the duration of the analysis. These data show that the subpial cell delivery technique is highly effective in populating the entire spinal cord with injected NSCs, and has a potential for clinical use in cell replacement therapies for the treatment of ALS, multiple sclerosis, or spinal cord injury.

Authors+Show Affiliations

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, California.Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, California. Department of Anesthesia, University of Ryukyus, Okinawa, Japan.Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, California. Department of Anesthesia, University of Ryukyus, Okinawa, Japan.Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, California.Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, Czech Republic.Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, Czech Republic.Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, California.Department of Biomaterials and Bioanalogous Systems, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.Department of Biomaterials and Bioanalogous Systems, Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic.Neuralstem Inc., Germantown, Maryland.Neuralstem Inc., Germantown, Maryland.Department of Anesthesia, University of Ryukyus, Okinawa, Japan.Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California.Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California.Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California.Department of Neurosurgery, University of California, San Diego, La Jolla, California.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31800978

Citation

Marsala, Martin, et al. "Spinal Parenchymal Occupation By Neural Stem Cells After Subpial Delivery in Adult Immunodeficient Rats." Stem Cells Translational Medicine, 2019.
Marsala M, Kamizato K, Tadokoro T, et al. Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats. Stem Cells Transl Med. 2019.
Marsala, M., Kamizato, K., Tadokoro, T., Navarro, M., Juhas, S., Juhasova, J., ... Ciacci, J. (2019). Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats. Stem Cells Translational Medicine, doi:10.1002/sctm.19-0156.
Marsala M, et al. Spinal Parenchymal Occupation By Neural Stem Cells After Subpial Delivery in Adult Immunodeficient Rats. Stem Cells Transl Med. 2019 Dec 4; PubMed PMID: 31800978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Spinal parenchymal occupation by neural stem cells after subpial delivery in adult immunodeficient rats. AU - Marsala,Martin, AU - Kamizato,Kota, AU - Tadokoro,Takahiro, AU - Navarro,Michael, AU - Juhas,Stefan, AU - Juhasova,Jana, AU - Marsala,Silvia, AU - Studenovska,Hana, AU - Proks,Vladimir, AU - Hazel,Tom, AU - Johe,Karl, AU - Kakinohana,Manabu, AU - Driscoll,Shawn, AU - Glenn,Thomas, AU - Pfaff,Samuel, AU - Ciacci,Joseph, Y1 - 2019/12/04/ PY - 2019/05/23/received PY - 2019/09/19/accepted PY - 2019/12/5/pubmed PY - 2019/12/5/medline PY - 2019/12/5/entrez KW - glia limitans formation from grafted neural precursors KW - human-specific mRNA sequencing KW - immunodeficient rat KW - neuraxial neural precursor migration KW - subpial stem cell injection JF - Stem cells translational medicine JO - Stem Cells Transl Med N2 - Neural precursor cells (NSCs) hold great potential to treat a variety of neurodegenerative diseases and injuries to the spinal cord. However, current delivery techniques require an invasive approach in which an injection needle is advanced into the spinal parenchyma to deliver cells of interest. As such, this approach is associated with an inherent risk of spinal injury, as well as a limited delivery of cells into multiple spinal segments. Here, we characterize the use of a novel cell delivery technique that employs single bolus cell injections into the spinal subpial space. In immunodeficient rats, two subpial injections of human NSCs were performed in the cervical and lumbar spinal cord, respectively. The survival, distribution, and phenotype of transplanted cells were assessed 6-8 months after injection. Immunofluorescence staining and mRNA sequencing analysis demonstrated a near-complete occupation of the spinal cord by injected cells, in which transplanted human NSCs (hNSCs) preferentially acquired glial phenotypes, expressing oligodendrocyte (Olig2, APC) or astrocyte (GFAP) markers. In the outermost layer of the spinal cord, injected hNSCs differentiated into glia limitans-forming astrocytes and expressed human-specific superoxide dismutase and laminin. All animals showed normal neurological function for the duration of the analysis. These data show that the subpial cell delivery technique is highly effective in populating the entire spinal cord with injected NSCs, and has a potential for clinical use in cell replacement therapies for the treatment of ALS, multiple sclerosis, or spinal cord injury. SN - 2157-6580 UR - https://www.unboundmedicine.com/medline/citation/31800978/Spinal_parenchymal_occupation_by_neural_stem_cells_after_subpial_delivery_in_adult_immunodeficient_rats L2 - https://doi.org/10.1002/sctm.19-0156 DB - PRIME DP - Unbound Medicine ER -