A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland Institute of Biomedicine, University of Oulu, Oulu, Finland Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland Department of Medicine, Kuopio University Hospital, Kuopio, Finland Department of Oncology, Kuopio University Hospital, Kuopio, Finland Medeia Therapeutics Ltd, Kuopio, Finland.
Accumulation of amyloid ß (Aß) is a major hallmark in Alzheimer's disease (AD). Bone marrow-derived monocytic cells (BMM) have been shown to reduce Aß burden in mouse models of AD, alleviating the AD pathology. BMM have been shown to be more efficient phagocytes in AD than the endogenous brain microglia. Because BMM have a natural tendency to infiltrate into the injured area, they could be regarded as optimal candidates for cell-based therapy in AD. In this study, we describe a method to obtain monocytic cells from BM-derived hematopoietic stem cells (HSC). Mouse or human HSC were isolated and differentiated in the presence of macrophage colony stimulating factor (MCSF). The cells were characterized by assessing the expression profile of monocyte markers and cytokine response to inflammatory stimulus. The phagocytic capacity was determined with Aß uptake assay in vitro and Aß degradation assay of natively formed Aß deposits ex vivo and in a transgenic APdE9 mouse model of AD in vivo. HSC were lentivirally transduced with enhanced green fluorescent protein (eGFP) to determine the effect of gene modification on the potential of HSC-derived cells for therapeutic purposes. HSC-derived monocytic cells (HSCM) displayed inflammatory responses comparable to microglia and peripheral monocytes. We also show that HSCM contributed to Aß reduction and could be genetically modified without compromising their function. These monocytic cells could be obtained from human BM or mobilized peripheral blood (PB) HSC, indicating a potential therapeutic relevance for AD.