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Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer’s disease mouse model

ABSTRACT: The conditions supporting the generation of microglia-like cells in the central nervous system (CNS) after transplantation of hematopoietic stem/progenitor cells (HSPC) have been extensively studied to advance the treatment of neurodegenerative disorders. Here, we challenge the HSPC transplantation paradigm by exploring different cell subsets and delivery routes with the goal of favoring the establishment of a robust and exclusive engraftment of HSPCs and their progeny in the CNS of transplant recipients. In this setting, we show that the CNS environment uniquely drives the expansion, distribution and myeloid differentiation of the locally transplanted cells towards a microglia-like phenotype. Importantly, intra-CNS transplantation of engineered HSPCs benefit 5xFAD Alzheimer’s disease mice, a finding that provides not only the first example of efficacy of HSPC gene therapy in this indication, but also a proof of the therapeutic potential of this novel approach that determines a CNS-restricted engraftment of the transplant progeny cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE275808 | GEO | 2024/08/28

REPOSITORIES: GEO

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Novel transplantation modalities for generating transcriptionally dependable new microglia from hematopoietic stem and progenitor cells

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Project description:Mesenchymal Stromal Cells (MSCs) have been employed in vitro to support HSPC expansion and in vivo to promote Hematopoietic Stem and Progenitor Cells (HSPCs) engraftment. Based on these studies, we developed an MSC-based co-culture system to optimize transplantation outcome of CRISPR-Cas9 gene-edited (GE) human HSPCs. We show that bone marrow (BM)-MSCs produce several hematopoietic supportive and anti-inflammatory factors capable to alleviate the proliferation arrest and mitigate the apoptotic and inflammatory programs activated in GE-HSPCs, improving their expansion and clonogenic potential in vitro. The use of BM-MSCs resulted in superior human engraftment and increased clonal output of GE-HSPCs contributing to the early phase of hematological reconstitution in the peripheral blood of transplanted mice. In conclusion, our work poses the biological bases for a novel clinical use of BM-MSCs to promote engraftment of GE-HSPCs and improve their transplantation outcome.

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