Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

Han, Jinming; Sarlus, Heela; Wszołek, Zbigniew K.; Karrenbauer, Virginija Danylaité; Harris, Robert A.

doi:10.1186/s40478-020-01093-3

Cited by 43 publications

(32 citation statements)

References 106 publications

(192 reference statements)

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“…Colony-stimulating factor 1 receptor ( CSF1R )-related leukoencephalopathy, mainly caused by CSF1R gene mutations and regarded as the most common type of adult-onset leukoencephalopathy, currently without a cure, typically presents with progressive neuropsychiatric and motor symptoms [ 47 , 48 ]. CSF1R is predominately expressed on microglia within the CNS and thus CSF1R -related leukoencephalopathy is considered as a primary CNS microgliopathy with dystrophic microglia playing a pivotal role in disease pathogenesis [ 47 , 49 ]. Although there are no sex differences of CSF1R -related leukoencephalopathy in prevalence and disease duration, male patients develop disease significantly later than do females [ 50 ].…”

Section: Sex Bias In Neurological Diseasesmentioning

confidence: 99%

Uncovering sex differences of rodent microglia

Han

Fan

Zhou

et al. 2021

J Neuroinflammation

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131

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There are inherent structural and functional differences in the central nervous systems (CNS) of females and males. It has been gradually established that these sex-specific differences are due to a spectrum of genetic, epigenetic, and hormonal factors which actively contribute to the differential incidences, disease courses, and even outcomes of CNS diseases between sexes. Microglia, as principle resident macrophages in the CNS, play a crucial role in both CNS physiology and pathology. However, sex differences of microglia have been relatively unexplored until recently. Emerging data has convincingly demonstrated the existence of sex-dependent structural and functional differences of rodent microglia, consequently changing our current understanding of these versatile cells. In this review, we attempt to comprehensively outline the current advances revealing microglial sex differences in rodent and their potential implications for specific CNS diseases with a stark sex difference. A detailed understanding of molecular processes underlying microglial sex differences is of major importance in design of translational sex- and microglia-specific therapeutic approaches.

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Section: Sex Bias In Neurological Diseasesmentioning

confidence: 99%

Uncovering sex differences of rodent microglia

Han

Fan

Zhou

et al. 2021

J Neuroinflammation

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131

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“…An alternative approach, of transplantation of genetically-engineered autologous hematopoietic stem cells, has proven to be beneficial in X-linked adrenoleukodystrophy [115,116]. Recently strategies for efficient microglial replacement therapy have been developed in mouse [117][118][119].…”

Section: Emerging Therapies For Crlmentioning

confidence: 99%

Modeling CSF‐1 receptor deficiency diseases – how close are we?

2021

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The role of colony stimulating factor-1 receptor (CSF-1R) in macrophage and organismal development has been extensively studied in mouse. Within the last decade mutations in the CSF1R have been shown to cause rare diseases of both pediatric (Brain Abnormalities, Neurodegeneration, and Dysosteosclerosis (BANDDOS), OMIM #618476) and adult [CSF1R-related leukoencephalopathy (CRL), OMIM #221820] onset. Here we review the genetics, penetrance and histopathological features of these diseases and discuss to what extent the animal models of Csf1r deficiency currently available provide systems in which to study the underlying mechanisms involved.

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“…Successful examples include the use of chimeric antigen receptor (CAR) T cells to treat patients with acute lymphoid leukemia, lymphoma and multiple myeloma and natural killer cells for acute myeloid leukemia, as well as the treatment of post-transplant leukemia relapse with donor lymphocyte infusions (DLIs) [1][2][3][4][5][6]. Furthermore, stem cell transplantation has proven successful in the treatment of hematological malignancies, autoimmune diseases, immune deficiencies, metabolic syndromes and the regeneration of tissues [4,[7][8][9][10]. However, several of these cell therapies remain unpredictable in terms of efficacy and potential side effects.…”

Section: Introductionmentioning

confidence: 99%

Optimisation of the Synthesis and Cell Labelling Conditions for [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS: a Direct In Vitro Comparison in Cell Types with Distinct Therapeutic Applications

et al. 2021

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Background There is a need to better characterise cell-based therapies in preclinical models to help facilitate their translation to humans. Long-term high-resolution tracking of the cells in vivo is often impossible due to unreliable methods. Radiolabelling of cells has the advantage of being able to reveal cellular kinetics in vivo over time. This study aimed to optimise the synthesis of the radiotracers [89Zr]Zr-oxine (8-hydroxyquinoline) and [89Zr]Zr-DFO-NCS (p-SCN-Bn-Deferoxamine) and to perform a direct comparison of the cell labelling efficiency using these radiotracers. Procedures Several parameters, such as buffers, pH, labelling time and temperature, were investigated to optimise the synthesis of [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS in order to reach a radiochemical conversion (RCC) of >95 % without purification. Radio-instant thin-layer chromatography (iTLC) and radio high-performance liquid chromatography (radio-HPLC) were used to determine the RCC. Cells were labelled with [89Zr]Zr-oxine or [89Zr]Zr-DFO-NCS. The cellular retention of 89Zr and the labelling impact was determined by analysing the cellular functions, such as viability, proliferation, phagocytotic ability and phenotypic immunostaining. Results The optimised synthesis of [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS resulted in straightforward protocols not requiring additional purification. [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS were synthesised with an average RCC of 98.4 % (n = 16) and 98.0 % (n = 13), respectively. Cell labelling efficiencies were 63.9 % (n = 35) and 70.2 % (n = 30), respectively. 89Zr labelling neither significantly affected the cell viability (cell viability loss was in the range of 1–8 % compared to its corresponding non-labelled cells, P value > 0.05) nor the cells’ proliferation rate. The phenotype of human decidual stromal cells (hDSC) and phagocytic function of rat bone-marrow-derived macrophages (rMac) was somewhat affected by radiolabelling. Conclusions Our study demonstrates that [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS are equally effective in cell labelling. However, [89Zr]Zr-oxine was superior to [89Zr]Zr-DFO-NCS with regard to long-term stability, cellular retention, minimal variation between cell types and cell labelling efficiency.

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Microglial replacement therapy: a potential therapeutic strategy for incurable CSF1R-related leukoencephalopathy

Cited by 43 publications

References 106 publications

Uncovering sex differences of rodent microglia

Uncovering sex differences of rodent microglia

Modeling CSF‐1 receptor deficiency diseases – how close are we?

Optimisation of the Synthesis and Cell Labelling Conditions for [89Zr]Zr-oxine and [89Zr]Zr-DFO-NCS: a Direct In Vitro Comparison in Cell Types with Distinct Therapeutic Applications

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