Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain

Sailor, Kurt A.; Agoranos, Georgios; López-Manzaneda, Sergio; Tada, Satoru; Gillet-Legrand, Béatrix; Guérinot, Corentin; Masson, Jean-Baptiste; Vestergaard, Christian; Bonner, Melissa; Gagnidze, Khatuna; Veres, Gábor; Lledo, Pierre-Marie; Cartier, Nathalie

doi:10.1038/s41591-022-01691-9

Cited by 44 publications

(47 citation statements)

References 47 publications

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“…The numbers of transgene‐carrying cells decreased with time in the lesion and perilesional areas, which could be explained by the fact that immune cells infiltrating CNS have been reported to eventually undergo apoptosis (Pender et al , 1991 ), or because these cells simply leave via defined lymphatic channels (Tavares & Louveau, 2021 ). Interestingly, we did observe the persistence of some GFP + cells in the lesions and perilesional tissue at 60 dpl, which is consistent with the reports that busulfan preconditioning increases CNS engraftment of blood myeloid cells (Capotondo et al , 2012 ; Sailor et al , 2022 ).…”

Section: Discussionsupporting

confidence: 92%

“…In this manner, OPC recruitment would be stimulated prior to the formation of glial scar, to promote remyelination thus preventing/reducing axonal loss. Interestingly, the treatment with busulfan, the drug used as a preconditioning treatment for HSCT, enhances CNS engraftment of blood monocytes derived from grafted HSCs, even in the absence of blood–brain barrier breakdown (Capotondo et al , 2012 ; Sailor et al , 2022 ). This explains the benefits of genetically modified HSCT described in patients with leukodystrophies, and suggests that: (i) MS lesions in the progressive phase (with no breakdown of blood–brain barrier) may also be targeted by transgene‐carrying blood monocytes to enhance remyelination and (ii) Blood cells that entered CNS during one attack may become established there, thus be available for another demyelinating episode.…”

Section: Discussionmentioning

confidence: 99%

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Genetically modified macrophages accelerate myelin repair

Aigrot

Barthelemy

Moyon³

et al. 2022

EMBO Mol Med

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Preventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents axonal degeneration, promoting this process in patients might enhance neuroprotection. In demyelinating mouse lesions, local overexpression of semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases remyelination. However, molecular targeting to MS lesions is a challenge. A clinically relevant paradigm for delivering Sema3F to demyelinating lesions could be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically modified hematopoietic stem cells (HSCs) as means of obtaining chimeric mice with circulating Sema3F-overexpressing monocytes. We demonstrated that Sema3F-transduced HSCs stimulate OPC migration in a neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion, which was conserved in middle-aged OPCs. While demyelinating lesions induced in mice with Sema3F-expressing blood cells showed no changes in inflammation and OPC survival, OPC recruitment was enhanced which accelerated the onset of remyelination. Our results provide a proof of concept that blood cells, particularly monocytes/macrophages, can be used to deliver pro-remyelinating agents "at the right time and place," suggesting novel means for remyelination-promoting strategies in MS.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Genetically modified macrophages accelerate myelin repair

Aigrot

Barthelemy

Moyon³

et al. 2022

EMBO Mol Med

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“…The strategy we are proposing relies on blood-derived macrophage infiltration in CNS lesions that are undergoing activity, both in RRMS and early progressive MS, while axons are still viable. Interestingly, the treatment with busulfan, the drug used as a pre-conditioning treatment for HSCT, enhances CNS engraftment of blood monocytes derived from grafted HSCs in the absence of blood-brain barrier breakdown 34,35 . This explains the benefits of genetically-modified HSCT described in patients with leukodystrophies, and suggests that MS lesions in the progressive phase (with no breakdown of blood-brain barrier) may also be targeted by transgene-carrying blood monocytes to enhance remyelination.…”

Section: Discussionmentioning

confidence: 99%

Genetically-Modified Macrophages Accelerate Myelin Repair

Tepavčević

Dufayet-Chaffaud

Aigrot

et al. 2020

Preprint

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Despite extensive progress in immunotherapies that reduce inflammation and relapse rate in patients with multiple sclerosis (MS), preventing disability progression associated with cumulative neuronal/axonal loss remains an unmet therapeutic need. Complementary approaches have established that remyelination prevents degeneration of demyelinated axons. While several pro-remyelinating molecules are undergoing preclinical/early clinical testing, targeting these to disseminated MS plaques is a challenge. In this context, we hypothesized that monocyte (blood) -derived macrophages may be used to efficiently deliver repair-promoting molecules to demyelinating lesions. Here, we used transplantation of genetically-modified hematopoietic stem cells (HSCs) to obtain circulating monocytes that overexpress Semaphorin 3F, a pro-remyelinating molecule. We show that Semaphorin 3F-expressing macrophages quickly infiltrate demyelinating spinal cord lesions, which increases oligodendrocyte progenitor cell recruitment and accelerates myelin repair. Our results provide a proof-of-concept that monocyte-derived macrophages could be used to deliver pro-remyelinating agents "at the right time and place", suggesting novel means for remyelinating therapies in patients with MS.

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“…Specific chemotherapy agents used in conditioning regimens before Allo-HSCT may result in the so-called “brain conditioning,” which creates a permissive niche for brain engraftment of donor-derived myeloid cells. Sailor et al (2022) have recently demonstrated that Busulfan, an alkylayting agent commonly used in conditioning regimens, causes host microglial senescence, cell cycle arrest and regenerative capacity exhaustion. This, in turn, results in more efficient trafficking of donor-derived macrophages to the brain that successfully engraft and become resident.…”

Section: Inborn Errors Of Metabolism With Neurological Involvementmentioning

confidence: 99%

“…This, in turn, results in more efficient trafficking of donor-derived macrophages to the brain that successfully engraft and become resident. The authors propose that when microglial cell loss reaches a critical density, the brain niche becomes permissive for donor cell engraftment ( Sailor et al, 2022 ). Capotondo et al (2012) also reported on Busulfan, showing that it depletes functionally defined microglia precursors in the brain, allowing increased turnover by donor-derived myeloid cells via CCR2 signaling.…”

Section: Inborn Errors Of Metabolism With Neurological Involvementmentioning

confidence: 99%

Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism

Vasconcelos

Lacerda

2022

Front. Cell. Neurosci.

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Hematopoietic stem cells have been investigated and applied for the treatment of certain neurological disorders for a long time. Currently, their therapeutic potential is harnessed in autologous and allogeneic hematopoietic stem cell transplantation (HSCT). Autologous HSCT is helpful in immune-mediated neurological diseases such as Multiple Sclerosis. However, clinical benefits derive more from the immunosuppressive conditioning regimen than the interaction between stem cells and the nervous system. Mainly used for hematologic malignancies, allogeneic HSCT explores the therapeutic potential of donor-derived hematopoietic stem cells. In the neurological setting, it has proven to be most valuable in Inborn Errors of Metabolism, a large spectrum of multisystem disorders characterized by congenital deficiencies in enzymes involved in metabolic pathways. Inborn Errors of Metabolism such as X-linked Adrenoleukodystrophy present with brain accumulation of enzymatic substrates that result in progressive inflammatory demyelination. Allogeneic HSCT can halt ongoing inflammatory neural destruction by replacing hematopoietic-originated microglia with donor-derived myeloid precursors. Microglia, the only neural cells successfully transplanted thus far, are the most valuable source of central nervous system metabolic correction and play a significant role in the crosstalk between the brain and hematopoietic stem cells. After transplantation, engrafted donor-derived myeloid cells modulate the neural microenvironment by recapitulating microglial functions and enhancing repair mechanisms such as remyelination. In some disorders, additional benefits result from the donor hematopoietic stem cell secretome that cross-corrects neighboring neural cells via mannose-6-phosphatase paracrine pathways. The limitations of allogeneic HSCT in this setting relate to the slow turnover of microglia and complications such as graft-vs.-host disease. These restraints have accelerated the development of hematopoietic stem cell gene therapy, where autologous hematopoietic stem cells are collected, manipulated ex vivo to overexpress the missing enzyme, and infused back into the patient. With this cellular drug vehicle strategy, the brain is populated by improved cells and exposed to supraphysiological levels of the flawed protein, resulting in metabolic correction. This review focuses on the mechanisms of brain repair resulting from HSCT and gene therapy in Inborn Errors of Metabolism. A brief mention will also be made on immune-mediated nervous system diseases that are treated with this approach.

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Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain

Cited by 44 publications

References 47 publications

Genetically modified macrophages accelerate myelin repair

Genetically modified macrophages accelerate myelin repair

Genetically-Modified Macrophages Accelerate Myelin Repair

Hematopoietic Stem Cell Transplantation for Neurological Disorders: A Focus on Inborn Errors of Metabolism

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