Bone marrow‐derived cells in the central nervous system of a mouse model of amyotrophic lateral sclerosis are associated with blood vessels and express CX₃CR1

Abstract

Amyotrophic lateral sclerosis (ALS) is associated with increased numbers of microglia within the CNS. However, it is unclear to what extent bone marrow (BM)-derived cells contribute to this microgliosis. We have studied the adoptive transfer of green fluorescent protein (GFP)-labeled whole BM cells and BM from mice that express GFP only in CX(3)CR1+ cells (CX(3)CR1(+/GFP)) into the CNS of a murine model of ALS having over-expression of mutant superoxide dismutase (mSOD), and wt littermates. We find that most GFP+ and CX(3)CR1(+/GFP) cells are found adjacent to the microvasculature within the CNS, both in mSOD and wt mice. GFP+ and CX(3)CR1(+/GFP) cells within the CNS have a variety of morphologies, including cells with an elongated appearance, weak Iba-1 immunoreactivity, and often mannose receptor immunoreactivity, indicating that these cells are perivascular microglia. Typically, less than 10% of BM-derived cells had a stellate-shape and expressed strong Iba-1 immunoreactivity, as expected for parenchymal microglia, indicating that BM-derived cells uncommonly generate parenchymal microglia. Adoptive transfer of BM-derived cells from CX(3)CR1(+/GFP) mice revealed that many elongated cells are GFP+, demonstrating that some perivascular cells are derived from BM cells of the CX(3)CR1+ lineage. The significantly greater numbers of BM cells in mSOD than in control mice indicate that the presence of these BM cells in the spinal cord is regulated by conditioning stimuli that may include irradiation and inflammatory factors within the CNS.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Our current work does not formally determine whether degenerating Iba1-positive cells are microglia and/or infiltrating monocytes. The extent of monocyte infiltration remains controversial in the field of ALS [9,12,42,1,46], contrary to Alzheimer's disease in which monocyte infiltration has been repeatedly observed [29,30]. Our gene expression results demonstrate consistent loss of El Oussini and collaborators 15 expression of multiple genes typical of homeostatic microglia but while the monocyte marker Ly6c1 remained unaffected (Fig 6).…”

“…An open question is whether the toxic effect of macrophages is mediated by resident microglia and/or by infiltrating blood monocytes. The extent of monocyte infiltration during ALS in mouse models remains controversial, with one study observing major monocytic infiltration [9], and others only very little if any [12,42,1,46]. Recently, genome-wide characterization of microglial and monocyte expression patterns led to the identification of a molecular signature of homeostatic microglia.…”

Submyeloablative conditioning with busulfan permits bone marrow-derived cell accumulation in a murine model of Alzheimer’s disease

“…Brain sections were analyzed using a Leica epifluorescence microscope with a Leica digital camera (Leica Microsystems, Germany). GFP + cells in the cortex, hippocampus and hypothalamus of 3 brain sections per mouse were manually counted as previously described [14]. The area of tissue evaluated was outlined using microscope analysis software and the cell density determined using the area measurement tool on the Leica microscope software (Leica Application Suite; Leica Microsystems, Switzerland) to determine the mean number of GFP + cells/mm 3 tissue.…”

Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity

“…Thus, in transgenic mice harboring mutant superoxide dismutase (mSOD), the murine model of amyotrophic lateral sclerosis (ALS), microglia are activated and infiltration of BM-derived cells into the CNS is observed [40,41]. In fact, it was suggested that reducing mSOD levels specifically in microglia might inhibit disease progression [42], implying detrimental microglial contribution in ALS.…”