title: Wild-type bone marrow transplant partially reverses neuroinflammation in progranulin-deficient mice.
abstract: Frontotemporal dementia (FTD) is a neurodegenerative disease with devastating changes in behavioral performance and social function. Mutations in the progranulin gene (GRN) are one of the most common causes of inherited FTD due to reduced progranulin expression or activity, including in brain where it is expressed primarily by neurons and microglia. Thus, efforts aimed at enhancing progranulin levels might be a promising therapeutic strategy. Bone marrow (BM)-derived cells are able to engraft in the brain and adopt a microglial phenotype under myeloablative irradiation conditioning. This ability makes BM-derived cells a potential cellular vehicle for transferring therapeutic molecules to the central nervous system. Here, we utilized BM cells from Grn(+/+) (wild type or wt) mice labeled with green fluorescence protein for delivery of progranulin to progranulin-deficient (Grn(-/-)) mice. Our results showed that wt bone marrow transplantation (BMT) partially reconstituted progranulin in the periphery and in cerebral cortex of Grn(-/-) mice. We demonstrated a pro-inflammatory effect in vivo and in ex vivo preparations of cerebral cortex of Grn(-/-) mice that was partially to fully reversed 5 months after BMT. Our findings suggest that BMT can be administered as a stem cell-based approach to prevent or to treat neurodegenerative diseases.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Macarena S
authors.initials: MS
authors.lastname: Aloi
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Eiron
authors.initials: E
authors.lastname: Cudaback
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Josephsen
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Rice
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Nikolas L
authors.initials: NL
authors.lastname: Jorstad
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002540:Cerebral Cortex / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000209:etiology / Q000628:therapy*; D000077155:Granulins; D056747:Immunomodulation; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D000077153:Progranulins
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins