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-derived cells are able to engraft in the brain and adopt a microglial phenotype under myeloablative irradiation conditioning. This ability makes bone marrow (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 five months after BMT. Our findings suggest that BMT can be administered as a stem cell-based approach to prevent or to treat neurodegenerative diseases.

High-throughput analysis of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing

“…As in our previous studies, we observed biodistribution via vector integration quantification and transgene expression in the BM and the brain for all treatment groups for LVV.GFP and LVV.GRN (Figures 8A, 8B LVV.GRN-treated groups, we measured supraphysiological levels of human progranulin via ELISA in the plasma and the BM, equivalent to an average of 5-to 11-fold above previously reported wild-type levels (Figures 8C and 8D). 42 We also observed human progranulin levels in whole-brain lysate of LVV.GRN-treated animals, equivalent to 30%-50% of previously reported mouse progranulin levels in the brain (Figure 8G). 43 Using immunohistochemical visualization of mouse and human progranulin, we observed progranulin+ cells in the cortex of LVV.GRN-treated homozygous mutant animals, consistent with the engraftment of LVV.GRN+ cells in the brain (Figure 8I).…”

Genetically engineered microglia-like cells have therapeutic potential for neurodegenerative disease

“…Across all LVV.GRN-treated groups, we measured supraphysiological levels of human progranulin via ELISA in the plasma and the bone marrow, equivalent to an average of 5-11-fold above previously reported wild-type levels (Fig. 8c, d) 42 . We also observed human progranulin levels in whole brain lysate of LVV.GRN-treated animals, equivalent to 30-50% of previously reported mouse progranulin levels in the brain (Fig.…”

CNS Repopulation by Hematopoietic-Derived Microglia-Like Cells Corrects Progranulin deficiency

“…Moreover, the symptoms of severe deficiency (CLN11) affect the CNS and retina, where high replacement of dysfunctional GRN-deficient microglia can be achieved. However, a previous study in which mice were conditioned with TBI, BMT showed only partial efficacy, likely due to the low recruitment of hematopoietic cells to the brain 91 . To evaluate the effectiveness of our optimized BU + PLX conditioning, we transplanted a Grn −/− mouse model 92 with either wild-type BM from CAG-GFP mice (Treated, WT BMT) or BM from a Grn −/− mice (Sham, KO BMT) mice.…”