title: Perivascular, but not parenchymal, cerebral engraftment of donor cells after non-myeloablative bone marrow transplantation.
abstract: Myeloablative (MyA) bone marrow transplantation (BMT) results in robust engraftment of BMT-derived cells in the central nervous system (CNS) and is neuroprotective in diverse experimental models of neurodegenerative diseases of the brain and retina. However, MyA irradiation is associated with significant morbidity and mortality and does not represent a viable therapeutic option for the elderly. Non-myeloablative (NMyA) BMT is less toxic, but it is not known if the therapeutic efficacy observed with MyA BMT is preserved. As a first step to address this important gap in knowledge, we evaluated and compared engraftment characteristics of BMT-derived monocytes/microglia using several clinically relevant NMyA pretransplant conditioning regimens in C57BL/6 mice. These included chemotherapy (fludarabine and cyclophosphamide) with or without 2 Gy irradiation, and 5.5 Gy irradiation alone. Each regimen was followed by transplantation of whole bone marrow from green fluorescent protein-expressing wild type (wt) mice. While stable hematopoietic engraftment occurred, to varying degrees, in all NMyA regimens, only 5.5 Gy irradiation resulted in significant engraftment of BMT-derived cells in the brain, where these cells were exclusively localized to perivascular, leptomeningeal, and related anatomic regions. Engraftment in retina under 5.5 Gy NMyA conditions was significantly reduced compared to MyA, but robust engraftment was identified in the optic nerve. Advancing the therapeutic applications of BMT to neurodegenerative diseases will require identification of the barrier mechanisms that MyA, but not NMyA, BMT is able to overcome.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.forename: Nikolas L
authors.initials: NL
authors.lastname: Jorstad
authors.forename: Christine
authors.initials: C
authors.lastname: Shiao
authors.forename: Makenzie K
authors.initials: MK
authors.lastname: Cherne
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Khademi
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002490:Central Nervous System / Q000166:cytology*; D003520:Cyclophosphamide / Q000494:pharmacology; D005720:Gamma Rays; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D019653:Myeloablative Agonists / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000637:transplantation; D019172:Transplantation Conditioning / Q000379:methods*; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019653:Myeloablative Agonists; D049452:Green Fluorescent Proteins; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine
keywords: AD; ALS; ANOVA; Alzheimer's disease; BMT; Bone marrow transplantation; CNS; Central nervous system; GCL; GFP; Gray; Gy; HBSS; Hank's Balanced Salt Solution; IPL; Irradiation; Microglia; MyA; NMyA; Non-myeloablative; OPL; PBS; amyotrophic lateral sclerosis; analysis of variance; bone marrow transplant; central nervous system; ganglion cell layer; green fluorescent protein; inner plexiform layer; myeloablative; non-myeloablative; outer plexiform layer; phosphate buffered saline; wild type; wt