Abstract:Background
Microglia, the primary resident myeloid cells of the brain, play critical roles in immune defense by maintaining tissue homeostasis and responding to injury or disease. However, microglial activation and dysfunction has been implicated in a number of central nervous system (CNS) disorders, thus developing tools to manipulate and replace these myeloid cells in the CNS is of therapeutic interest.
Methods
Using whole body irr… Show more
“…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.…”
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.
“…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
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.
“…4f). Genes enriched in MLCs include Apobec1 and Ms4a14, markers that have been previously associated with BM-derived, CNS/PNS-associated macrophages when compared to endogenous microglia 31,32 . Gene Ontology (GO) and pathway analysis comparing the two populations highlight differences in genes associated with immune function, including chemokine production, cell adhesion, and responses to interferon, which is consistent with the functional role of microglia and MLCs in the brain (Supp.…”
Section: Hspc-derived Mlcs Are Highly Similar But Are Transcriptionally Distinguishable From Endogenous Microgliamentioning
Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) results in the engraftment of genetically modified microglia-like cells (MLCs) in the brain. While HSPC-GT has shown a clear neurological benefit in the clinic for specific rare diseases, the nature of MLC engraftment in the brain and the functional characteristics of MLCs remain contentious. Here we comprehensively characterized how different routes of administration affect the engraftment and biodistribution of genetically engineered HSPC-derivatives in mice. Using high-throughput single-cell profiling, we show that MLCs bear a transcriptional signature similar to resident microglia rather than invading macrophages. However, MLCs could clearly be distinguished from resident microglia by expression of a specific set of genes. Finally, in murine models of Parkinson's disease and frontotemporal dementia, we demonstrate that MLCs can provide therapeutically relevant levels of protein to the brain, thereby potentially opening avenues of HSPC-GT to address the underlying disease etiology of these and other similar disorders.
CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia caused by colony stimulating factor 1 receptor (CSF1R) gene mutations. The disease has a global distribution and currently has no cure. Individuals with CSF1R-related leukoencephalopathy variably present clinical symptoms including cognitive impairment, progressive neuropsychiatric and motor symptoms. CSF1R is predominantly expressed on microglia within the central nervous system (CNS), and thus CSF1R-related leukoencephalopathy is now classified as a CNS primary microgliopathy. This urgent unmet medical need could potentially be addressed by using microglia-based immunotherapies. With the rapid recent progress in the experimental microglial research field, the replacement of an empty microglial niche following microglial depletion through either conditional genetic approaches or pharmacological therapies (CSF1R inhibitors) is being studied. Furthermore, hematopoietic stem cell transplantation offers an emerging means of exchanging dysfunctional microglia with the aim of reducing brain lesions, relieving clinical symptoms and prolonging the life of patients with CSF1R-related leukoencephalopathy. This review article introduces recent advances in microglial biology and CSF1R-related leukoencephalopathy. Potential therapeutic strategies by replacing microglia in order to improve the quality of life of CSF1R-related leukoencephalopathy patients will be presented.
“…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].…”
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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