Munro DA, Bestard-Cuche N, McQuaid C, Chagnot A, Shabestari SK, Chadarevian JP, Maheshwari U, Szymkowiak S, Morris K, Mohammad M, Corsinotti A, Bradford B, Mabbott N, Lennen RJ, Jansen MA, Pridans C, McColl BW, Keller A, Blurton-Jones M, Montagne A, Williams A, Priller J. Microglia protect against age-associated brain pathologies. Neuron. 2024 Jun 17; PubMed.
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VIB-KU Leuven
VIB-KU Leuven
The two articles published back-to-back propose the exciting therapeutic concept that microglial transplantation can potentially rescue brain defects induced by the congenital lack of microglia. Both papers agree that the lack of microglia in adult mice results in neurodegeneration, brain calcifications, and myelin abnormalities, phenotypes resembling CSF1R-related leukoencephalopathy. Transplantation of wild-type mouse/human microglia rescued these phenotypes and protected against the development of the associated pathologies.
This is a very interesting strategy for primarily myeloid cells diseases, such as those caused by mutations in colony stimulating factor 1 receptor (CSF1R), which lead to defective maturation, proliferation, and survival of microglia and other tissue-resident macrophages. Although both papers are elegant and show striking effects in the model systems used, there are many things to consider if one wanted to envision microglial transplantations as a therapeutic. For example, in the context of CSF1R mutations, there is a strong contribution of tissue-resident macrophages outside the CNS that should be further explored in follow-up publications.
In addition, when thinking of translational aspects, correcting mutant stem cells and transplanting them back autologously, as shown by Chadarevian, is very interesting because it would avoid potential graft versus host disease that might happen after an allogeneic transplant. It also has downsides. It would require individual intervention for every single patient, which cannot be generalized. There are, of course, additional obstacles that should be considered, including safety, routes of delivery, etc., before this could be applied clinically.
Using microglia replacement as a cell therapy is not necessarily limited to CSF1R-related diseases but could also be applied to other microgliopathies/macrophage disorders. For instance, Nasu-Hakola is caused by defects in the myeloid-expressing gene, TREM2/DAP12, resulting in microglial/macrophage dysfunction.
Overall, we congratulate the authors on these two papers. They reinforce the role of microglia in neurodegeneration and open microglia transplantation strategies as new ways to treat microgliopathies.
View all comments by Anna Martinez-MurianaVIB-KU Leuven Center for Brain & Disease Research
UK Dementia Research Institute@UCL and VIB@KuLeuven
These two fascinating publications build on the landmark paper that demonstrated the generation of a mouse completely devoid of microglia by simply removing a specific enhancer in the promoter of the CSFR1 gene (Rojo et al., 2019). The surprise at that time was that the brains of these “FIRE” mice appeared relatively normal, raising numerous questions about the role of microglia in brain development. The current publications focus on the effects of this deficiency in later life. FIRE mice exhibit many features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a primary microgliopathy caused by mutations in the CSF1R gene. The two papers demonstrate that the transplantation of both primary mouse microglia and human microglia leads to complete microglia engraftment in the brain and protects against the observed pathologies.
These results provide preclinical evidence that microglia transplantation in the brain could be a powerful therapeutic approach for patients with primary microgliopathies. One reason this approach might be successful in ALSP patients is the reduced microglia numbers and proliferation, creating “empty niches” that can be colonized by the transplanted microglia. In other conditions, where microglia numbers are not affected, treatments to deplete endogenous microglia before transplantation may be necessary. It is also enticing to consider microglia transplantation for other neurological diseases, such as Alzheimer’s disease, which can be exacerbated by severe microglia deficiencies seen with TREM2 mutations. Recent evidence suggests that certain microglia genotypes (e.g., APOE3 Christchurch) (Chen et al., 2024; Arboleda-Velasquez et al., 2019) may be protective in Alzheimer’s. Therefore, one could speculate about microglia replacement in AD using microglia with protective genotypes.
These suggestions remain futuristic for now. We still lack a clear understanding of the precise role of microglia in Alzheimer’s , and the practical challenges of implementing cell therapies in humans will require significant and persistent research efforts.
More immediately, the work described in these two papers will likely benefit basic research. The promising news is that early transplantation of microglia in these FIRE mice can prevent many of the symptoms associated with aging. This presents an exciting opportunity to investigate the role of microglia and their diverse signaling pathways in brain function in unprecedented ways. We anticipate a surge of publications based on this model in the coming years.
References:
Rojo R, Raper A, Ozdemir DD, Lefevre L, Grabert K, Wollscheid-Lengeling E, Bradford B, Caruso M, Gazova I, Sánchez A, Lisowski ZM, Alves J, Molina-Gonzalez I, Davtyan H, Lodge RJ, Glover JD, Wallace R, Munro DA, David E, Amit I, Miron VE, Priller J, Jenkins SJ, Hardingham GE, Blurton-Jones M, Mabbott NA, Summers KM, Hohenstein P, Hume DA, Pridans C. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat Commun. 2019 Jul 19;10(1):3215. PubMed.
Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.
Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, Saez-Torres KL, Amarnani D, Schultz AP, Sperling RA, Leyton-Cifuentes D, Chen K, Baena A, Aguillon D, Rios-Romenets S, Giraldo M, Guzmán-Vélez E, Norton DJ, Pardilla-Delgado E, Artola A, Sanchez JS, Acosta-Uribe J, Lalli M, Kosik KS, Huentelman MJ, Zetterberg H, Blennow K, Reiman RA, Luo J, Chen Y, Thiyyagura P, Su Y, Jun GR, Naymik M, Gai X, Bootwalla M, Ji J, Shen L, Miller JB, Kim LA, Tariot PN, Johnson KA, Reiman EM, Quiroz YT. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019 Nov;25(11):1680-1683. Epub 2019 Nov 4 PubMed.
View all comments by Bart De StrooperDZNE
These two excellent studies explore FIRE mice to model rare autosomal-dominant leukodystrophy (ALSP). FIRE mice carry a homozygous loss of the key microglial-regulating gene CSF1R, and thus lack microglia. Of note, most ALSP patients carry a heterozygous CSFR1 mutation. However, modelling the heterozygous state in mice seems not to be sufficient to trigger ALSP-like neuropathology, motivating the authors to focus on the complete loss of CSF1R signalling in microglia.
Chadarevian et al. generated and characterized xenotolerant mice (hFIRE) to enable transplantation of human microglia, while Munro et al. used a previously published non-humanized FIRE mouse (Rojo et al., 2019) or their study. Both report ALSP-like neuropathological hallmarks, such as axonal spheroids, white-matter abnormalities, astrogliosis, and brain calcifications that develop during aging.
Surprisingly, microglial depletion did not provoke major differences in transcriptomic signatures of other brain cells at the young age of 6-7 weeks (Munro et al.). However, upon aging, transcriptional alterations were captured in oligodendrocytes and astrocytes, but not in neurons. It remains open whether this is a technical limitation reflecting the low neuronal coverage of the scRNA-sequencing datasets (Munro et al.) or whether the neuronal transcriptional network is indeed less sensitive to the lifelong absence of microglia.
Beyond the relevance of this work for ALSP, both studies support a concept that microglial loss of function is sufficient to trigger pathology in other brain cells over time, supporting a key role of microglia in maintaining brain homeostasis during aging. Notably, both report a subtle and regional neuronal loss (thalamus), supporting the idea that lack of microglial function alone is insufficient to provoke major and widespread neurodegeneration.
The question of cell- and region-specific sensitivity is an important aspect reflected in both studies. Thalamus and white matter appear as hot-spot pathological regions in FIRE mice. As the CSF1R depletion is present in all microglia, and microglial loss is not region-selective, differences are likely attributable to intercellular cross talk and regional vulnerabilities of other brain cells. In contrast to neuronal loss, axonal spheroids were observed throughout the brain (Chadarevian et al.), supporting the relevance of microglia for axonal health. Thus, a pathological cross talk of microglia to oligodendrocytes, astrocytes, and neurons—that is well supported by both studies—is an exciting feature that should be further mechanistically dissected.
Both have convincingly shown that transplantation of healthy human (Chadarevian et al.) or rodent (Munro et al.) microglia prevents the development of age-associated brain abnormalities. Furthermore, the work of Chadarevian and colleagues provides evidence that transplantation of ALSP patient-corrected microglia can also reverse some of the disease phenotypes. These studies pave the road to clinical translation because the primary microgliopathy ALSP provides an ideal setting to test the potential of microglia transplantation strategies. The findings clearly suggest the preventive potential of microglial transplantation and prove that microglial loss of function is the disease-triggering factor in ALSP.
What remains challenging is to evaluate microglial repair potential when disease pathology is fully established, as it is in ALSP patients. Furthermore, more work is needed to characterize possible detrimental effects of the remaining “ill” microglia in the brain and their interaction with the transplanted healthy microglia. Because some of the pathological hallmarks of ALSP, including cognitive and motor disturbances, were not recapitulated in FIRE mice, it raises the question whether some “ill” microglia that remain in the brains of ALSP patients may, in addition to the microglial loss of function, provoke further neuropathology.
Considering the important contribution of microglia to brain diseases, microglia transplantation is an extremely dynamic and exciting research area with a translational potential beyond ALSP.
References:
Rojo R, Raper A, Ozdemir DD, Lefevre L, Grabert K, Wollscheid-Lengeling E, Bradford B, Caruso M, Gazova I, Sánchez A, Lisowski ZM, Alves J, Molina-Gonzalez I, Davtyan H, Lodge RJ, Glover JD, Wallace R, Munro DA, David E, Amit I, Miron VE, Priller J, Jenkins SJ, Hardingham GE, Blurton-Jones M, Mabbott NA, Summers KM, Hohenstein P, Hume DA, Pridans C. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat Commun. 2019 Jul 19;10(1):3215. PubMed.
View all comments by Sabina TahirovicMax Planck Institute for Multidisciplinary Sciences
These two exciting papers by Munro et al. and Chadarevian et al. significantly advance our understanding of microglial function in maintaining brain integrity, demonstrating that these remarkable cells play a crucial role in preventing more pathological alterations than previously suspected.
Microglia, the brain’s resident immune cells, maintain tissue homeostasis by constantly surveilling the brain parenchyma. During development and in disease states, microglia adopt specific signatures tailored to meet these diverse challenges. Further understanding of such cellular responses and their associated repair processes is essential, as efficient and timely restoration of brain function is vital for delaying the progression of neurodegenerative diseases. However, in certain disease conditions often linked to aging, microglial states transition to profiles that exacerbate disease, promoting neurodegeneration and pathology. Rejuvenating aged microglia has emerged as a therapeutic strategy in experimental models of neurological disease.
Colony-stimulating factor 1 (CSF1) receptor signaling is crucial for microglial survival, as demonstrated by various genetic and pharmacological experiments. These findings in rodents are paralleled by CSF1 receptor-related human leukoencephalopathies. The two studies employ an elegant genetic tool that specifically targets the Csf1r FIRE enhancer leading to the absence of CNS microglia and a subset of peripheral macrophages.
Munro et al. investigated the impact of the permanent absence of murine microglia on long-term brain integrity. Chadarevian et al. used immune-compromised microglial mutants to explore the relationship between pathogenesis and grafted human iPSC microglia. They observed that brain aging is significantly accelerated in microglial mutants and focused on brain calcification as a newly recognized age-related pathological condition. Brain calcifications predominantly develop in thalamic nuclei and are associated with the neurovascular unit, especially dysfunctional pericytes. In the long run, calcium deposits can lead to microhemorrhages and microinfarcts. Previous studies suggested that defective calcium and phosphate metabolism, in addition to an osteoclast-like/pro-mineralizing state, could be causal for this histopathology. Surprisingly, Munro et al. found only very few mural and myeloid cell clusters that expressed the respective gene set, leaving the origin of calcium phosphate deposits unresolved.
Interestingly, transplantation of intact microglia, either of murine or human origin, largely prevented neurodegeneration and calcification. Thus, the authors conclude that microglia are instrumental in clearing calcium phosphate deposits. Both publications demonstrate the remarkable ability of grafted microglial progenitors to colonize the entire mouse brain, adopt homeostatic signatures, and functionally integrate. The authors propose that microglia transplantation could provide a therapeutic avenue to combat neuropathological conditions. Future studies will determine whether transplantation can serve as a therapeutic means to replace dysfunctional or neurotoxic microglia.
Together, these important studies from the Priller and Burton-Jones labs link microglial function to the prevention of accelerated neurodegeneration and suggest that long-term pharmacological depletion of microglia in neurological conditions should be approached with caution.
View all comments by Gesine SaherMake a Comment
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