Production of monocytic cells from bone marrow stem cells: therapeutic usage in Alzheimer’s disease

Abstract

Accumulation of amyloid β (Aβ) is a major hallmark in Alzheimer’s disease (AD). Bone marrow derived monocytic cells (BMM) have been shown to reduce Aβ 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 haematopoietic 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 Aβ uptake assay in vitro and Aβ degradation assay of natively formed Aβ 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 Aβ reduction and could be genetically modified without compromising their function. These monocytic cells could be obtained from human BM or mobilized peripheral blood HSC, indicating a potential therapeutic relevance for AD.

Hematopoietic CC-Chemokine Receptor 2 (CCR2) Competent Cells Are Protective for the Cognitive Impairments and Amyloid Pathology in a Transgenic Mouse Model of Alzheimer’s Disease

“…Chimeric mice: irradiation and bone marrow transplantation. Male APP Swe /PS1 and APP Swe /PS1/CCR2 -/-mice, 2.5-3 months of age, were exposed to 10 Gy total-body irradiation using a 60 Co source (Theratron-780 Irradiated mice transplanted with the cell suspension were housed in autoclaved cages and treated with antibiotics (0.2 mg trimethoprim and 1 mg sulfamethoxazole/mL drinking water given for 7 d before and 2 wks after irradiation). Animals (n = 77) were submitted to behavioral tests 3 months after transplantation and then killed for brain analyses.…”

“…Bone marrow-derived microglial cells have the ability to phagocytize Aβ, and oligomeric, protofibrillar and fibrillar amyloid can be removed by microglia depending on the context (45,(56)(57)(58)(59). Although HSC-derived monocytic cells share common characteristics with microglia and peripheral monocytes, they reduce Aβ faster than microglia (60). These bone marrow-derived cells infiltrate into nonirradiated brain (61) suggesting that CCR2-deficient microglia do not phagocytize and clear soluble Aβ.…”

Introduction to Stem Cells and Regenerative Medicine

“…Presently, regenerative medicine is a major focus of research not only to find therapies but also to understand basic biology and the pathogenesis of disease [18,19,20]. Although a number of ethical issues have arisen in stem cell research [21], recent advances in stem cell isolation and development have helped scientists to identify and culture specific cell types for regeneration of tissue in various disorders such as Parkinson’s [22], Alzheimer’s [23], or diseases of the heart [24], muscles [25], lung [26,27], liver [28], and other organs [14]. …”

Myeloid cell-based therapies in neurological disorders: How far have we come?

“…In a landmark study by Rivest and colleagues, BMDCs and not resident microglia had the ability to eliminate amyloid deposits by a cell-specific phagocytic mechanism in AD transgenic mice [85]. HSC-derived monocytic cells obtained from human and mouse BM were found to reduce Aβ burden by phagocytosis in AD transgenic mice [86].…”