Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Hohsfield, Lindsay A.; Najafi, Allison R.; Ghorbanian, Yasamine; Soni, Neelakshi; Hingco, Edna E.; Kim, Sung Jin; Jue, Ayer Darling; Swarup, Vivek; Inlay, Mathew A.; Green, Kim N.

doi:10.1186/s12974-020-01931-0

Cited by 38 publications

(43 citation statements)

References 93 publications

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“…In particular, long-term effects of microglia replacement are now not well understood. To that end, a recent study found subtle changes in transcriptional, histological, and behavioral features of mice with high CDMC chimerism (16). It is further possible that CDMCs mount a different immune response to CNS pathology than microglia.…”

Section: Discussionmentioning

confidence: 99%

Treatment of a genetic brain disease by CNS-wide microglia replacement

et al. 2022

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Hematopoietic cell transplantation after myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. The high chimerism resulted from a competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells, but not immediate myeloid or monocyte progenitor cells, contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential, we applied microglia replacement to a mouse model for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.

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Section: Discussionmentioning

confidence: 99%

Treatment of a genetic brain disease by CNS-wide microglia replacement

et al. 2022

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“…Following recovery, we explored co-localization of MAC2 expression in GFP+ cells in the adult mouse brains of long-term GFP BM chimeric mice and long-term GFP BM chimeric mice that underwent colony-stimulating factor 1 receptor inhibitor (CSF1Ri)-induced myeloid cell depletion and repopulation (~6 months following CSF1Ri treatment and CNS engraftment) (Figure 2a). In a previous study, we demonstrated that irradiation/BM transplant followed by CSF1Ri treatment results in substantial replacement of the microglial compartment with BM-derived monocytes (Hohsfield et al, 2020), providing a model to evaluate long-term and brain-wide BM-derived monocyte/macrophage engraftment.…”

Section: Mac2 Is a Specific And Long-lasting Marker For Bone Marrow-d...mentioning

confidence: 99%

MAC2 is a long‐lasting marker of peripheral cell infiltrates into the mouse CNS after bone marrow transplantation and coronavirus infection

Hohsfield

Tsourmas

Ghorbanian

et al. 2022

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Microglia are the primary resident myeloid cells of the brain responsible for maintaining homeostasis and protecting the central nervous system (CNS) from damage and infection. Monocytes and monocyte-derived macrophages arising from the periphery have also been implicated in CNS pathologies, however, distinguishing between different myeloid cell populations in the CNS has been difficult. Here, we set out to develop a reliable histological marker that can assess distinct myeloid cell heterogeneity and functional contributions, particularly in the context of disease and/or neuroinflammation. scRNAseq from brains of mice infected with the neurotropic JHM strain of the mouse hepatitis virus (JHMV), a mouse coronavirus, revealed that Lgals3 is highly upregulated in monocyte and macrophage populations, but not in microglia. Subsequent immunostaining for galectin-3 (encoded by Lgals3), also referred to as MAC2, highlighted the high expression levels of MAC2 protein in infiltrating myeloid cells in JHMV-infected and bone marrow (BM) chimeric mice, in stark contrast to microglia, which expressed little to no staining in these models. Expression of MAC2 was found even 6-10 months following BM-derived cell infiltration into the CNS. We also demonstrate that MAC2 is not a specific label for plaqueassociated microglia in the 5xFAD mouse model, but only appears in a distinct subset of these cells in the presence of JHMV infection or during aging. Our data suggest that MAC2 can serve as a reliable and long-lasting histological marker for monocyte/ macrophages in the brain, identifying an accessible approach to distinguishing resident microglia from infiltrating cells in the CNS under certain conditions.

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“…The recent wave of studies characterizing microglia at single-cell resolution indicate extensive transcriptional heterogeneity during development and disease, with a more homogeneous population evident in the homeostatic adult brain [5-7, 23, 24]. If an empty niche is available in the tissue myeloid compartment, cues from the local microenvironment can reprogram infiltrating bone marrow-derived monocytes or ontogenically foreign macrophages into microglialike phenotypes [25][26][27][28][29][30]. The extent of transcriptional reprogramming appears to depend on the yolk-sac or hematopoietic origin of the cell in question [8,26], at least in the CNS, where the adult resident macrophage population (e.g., microglia) derives from yolksac erythromyeloid progenitors [31][32][33][34].…”

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confidence: 99%

Microglia as hackers of the matrix: sculpting synapses and the extracellular space

et al. 2021

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Microglia shape the synaptic environment in health and disease, but synapses do not exist in a vacuum. Instead, pre- and postsynaptic terminals are surrounded by extracellular matrix (ECM), which together with glia comprise the four elements of the contemporary tetrapartite synapse model. While research in this area is still just beginning, accumulating evidence points toward a novel role for microglia in regulating the ECM during normal brain homeostasis, and such processes may, in turn, become dysfunctional in disease. As it relates to synapses, microglia are reported to modify the perisynaptic matrix, which is the diffuse matrix that surrounds dendritic and axonal terminals, as well as perineuronal nets (PNNs), specialized reticular formations of compact ECM that enwrap neuronal subsets and stabilize proximal synapses. The interconnected relationship between synapses and the ECM in which they are embedded suggests that alterations in one structure necessarily affect the dynamics of the other, and microglia may need to sculpt the matrix to modify the synapses within. Here, we provide an overview of the microglial regulation of synapses, perisynaptic matrix, and PNNs, propose candidate mechanisms by which these structures may be modified, and present the implications of such modifications in normal brain homeostasis and in disease.

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Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS

Cited by 38 publications

References 93 publications

Treatment of a genetic brain disease by CNS-wide microglia replacement

Treatment of a genetic brain disease by CNS-wide microglia replacement

MAC2 is a long‐lasting marker of peripheral cell infiltrates into the mouse CNS after bone marrow transplantation and coronavirus infection

Microglia as hackers of the matrix: sculpting synapses and the extracellular space

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