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

Barr, Christine; Manning, John; Lewis, Coral Ann B.; Rossi, Fábio; Krieger, Charles

doi:10.1016/j.neulet.2015.01.023

Cited by 9 publications

(13 citation statements)

References 30 publications

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“…These assumptions were made on the basis of cell transplantation experiments in rodents starting in the 1980s 9, 10 . Just recently, chemotherapeutical conditioning additionally suggested that perivascular macrophages were present in the CNS parenchyma after BM transplantation 11, 12 . However, all of these studies used either irradiation or chemotherapy as conditioning regimens thereby inducing an artificial influx of injected BM-derived cells due to damage of the blood-brain barrier and local induction of chemoattractants in the host CNS 13–15 .…”

Section: Introductionmentioning

confidence: 99%

Origin, fate and dynamics of macrophages at central nervous system interfaces

et al. 2016

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Perivascular, meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It has been assumed that they have a high turnover with blood-borne monocytes. However, large scale single-cell RNA-sequencing reveals a striking molecular overlap between perivascular macrophages and microglia but not monocytes. Using several fate mapping approaches and parabiosis we demonstrate that CNS macrophages arise from yolk sac precursors during embryonic development and remain a stable population. Notably, the generation of CNS macrophages relies on the transcription factor Pu.1 whereas myb, Batf3 and Nr4a1 are not required. Upon autoimmune inflammation, macrophages undergo extensive self-renewal by local proliferation. Our data provide challenging new insights into brains innate immune system.

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Section: Introductionmentioning

confidence: 99%

Origin, fate and dynamics of macrophages at central nervous system interfaces

et al. 2016

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“…Fractionated doses of 20 mg/kg/day of BU were administered via intraperitoneal injections until a total dose of 60–100 mg/kg was delivered as we have done previously (3, 11, 12). For a total dose of 125 mg/kg, fractionated doses of 25 mg/kg/day were administered for 5 days (4).…”

Section: Methodsmentioning

confidence: 99%

“…GFP + cells were quantified in five individual lumbar spinal cord sections separated by at least 150 μm as we have done previously (2, 3, 12, 27). The morphology of the GFP + cells was classified according to Vallières and Sawchenko (28).…”

Section: Methodsmentioning

confidence: 99%

“…Busulfan (BU) is a clinically approved bifunctional alkylating agent that depletes non-cycling primitive stem cells in the BM and has weak immunosuppressive properties (7). We and others have found that conditioning with BU prior to BMT leads to high levels of BM chimerism and accumulation of BMDCs within the CNS (2–4, 8–12). In fact, Wilkinson et al have claimed that BU conditioning enhances engraftment of BMDCs compared to whole-body lethal irradiation when using a higher dose of BU (125 mg/kg), than we and others have used previously (4).…”

Section: Introductionmentioning

confidence: 90%

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Bone Marrow-Derived Cell Accumulation in the Spinal Cord Is Independent of Peripheral Mobilization in a Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2017

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Bone marrow-derived cells (BMDCs) are capable of migrating across the blood–brain barrier (BBB) and accumulating in the central nervous system (CNS) when transplanted into recipients conditioned with whole-body irradiation or chemotherapy. We used the chemotherapeutic agents busulfan and treosulfan to condition recipient mice for transplantation with bone marrow (BM) cells isolated from donor mice ubiquitously expressing green fluorescent protein. We attempted to increase the accumulation of BMDCs in the CNS by mobilization of BMDCs using either, or both, granulocyte colony-stimulating factor (GCSF) or plerixafor (AMD3100). We also used several concentrations of busulfan. We hypothesized that higher concentrations of busulfan and BMDC mobilization would increase numbers of GFP+ cells in the CNS. The doses of busulfan employed (60–125 mg/kg) all resulted in high levels of sustained chimerism (>85% 1 year post-transplant) in both the blood and BM of wild-type (WT) mice and an amyotrophic lateral sclerosis (ALS) mouse model. Moreover, cells accumulated within the CNS in a dose-, time-, and disease-dependent manner. Conditioning with the hydrophilic busulfan analog treosulfan, which is unable to cross the BBB efficiently, also resulted in a high degree of BM chimerism. However, few GFP+ BMDCs were found within the CNS of WT or ALS mice of treosulfan-conditioned mice. Mobilization of BMDCs into the circulation using GCSF and/or AMD3100 did not lead to increased accumulation of GFP+ BMDCs within the CNS of WT or ALS mice. Weekly analysis of BMDC accumulation revealed that BMDCs accumulated more rapidly and to a greater extent in the CNS of ALS mice conditioned with a high dose (125 mg/kg) of busulfan compared to a lower dose (80 mg/kg). The number of GFP+ BMDCs in the CNS labeling with the proliferation marker Ki67 increased in parallel with BMDC accumulation within the CNS. Our results indicate that establishment of high levels of blood and BM chimerism alone is not sufficient to induce BMDC accumulation within the CNS and that CNS conditioning is a crucial requirement for BMDC accumulation to occur. Moreover, it appears that proliferation of BMDCs that infiltrate the CNS is partly responsible for cell accumulation in busulfan-conditioned ALS mice.

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“…antibody has recently been demonstrated to permit perivascular BMDC accumulation in the CNS of AD transgenic mice [91]. The therapeutic administration of BMDCs in AD is further encouraged by preclinical findings of a complete arrest in amyloid deposition after adoptive…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

Böttcher¹,

Priller²

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The pathogenesis of neurological disorders such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) is multifactorial and incompletely understood. The development of therapies for these disorders of the central nervous system (CNS) is thus far very challenging. Neuroinflammation is one of the processes that contribute to the pathogenesis of CNS diseases, and therefore represents an important therapeutic target. Myeloid cells derived from the bone marrow are ideal candidates for cell therapy in the CNS as they are capable of targeting the brain and providing neuroprotective and anti-inflammatory effects. In this review, experimental and clinical evidence for the therapeutic potential of myeloid cells in neurological disorders will be discussed. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

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

Cited by 9 publications

References 30 publications

Origin, fate and dynamics of macrophages at central nervous system interfaces

Origin, fate and dynamics of macrophages at central nervous system interfaces

Bone Marrow-Derived Cell Accumulation in the Spinal Cord Is Independent of Peripheral Mobilization in a Mouse Model of Amyotrophic Lateral Sclerosis

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

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