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Monocyte-derived microglia with Dnmt3a mutation cause motor pathology in aging mice

Kim et al. (BioRxiv) DOI:10.1101/2023.11.16.567402

Monocyte-derived microglia with Dnmt3a mutation cause motor pathology in aging mice

Keywords

  • Monocyte-derived macrophages

  • Dnmt3a mutation

  • Clonal hematopoiesis (CH)


Main Findings

Microglia, originating during embryogenesis, establish a self-contained cellular domain resilient against infiltration from adult definitive hematopoiesis, serving as vital guardians of brain homeostasis. However, the authors findings reveal an unforeseen occurrence within the aging mouse brain. Monocyte-derived macrophages (MoMΦ) exhibit a unique spatial preference by favouring areas such as the nigrostriatum and medulla while notably avoiding colonization of the frontal cortex. Remarkably, these parenchymal MoMΦ seamlessly adopt expression profiles akin to bona fide microglia, introducing a novel subset—monocyte-derived microglia. Originating from hematopoietic sources, MoMΦ become targets of clonal hematopoiesis (CH).

In a chimeric transfer model, the study illustrates the pathogenic potential of MoMΦ expressing Dnmt3aR822H, a prevalent mutation in human CH. These pathogenic MoMΦ, when accumulated, actively contribute to motor deficits reminiscent of atypical Parkinsonian disorders. The mouse model establishes a progressive seeding of MoMΦ within the aging healthy mouse brain, selective accumulation in distinct regions, and the capacity to induce brain pathology when harbouring somatic mutations associated with CH.

This integration of developmental insights and the emergent role of MoMΦ in the aging brain, coupled with the ramifications of Dnmt3a mutations, underscores the intricate interplay between microglial origins, clonal hematopoiesis, and neurodegenerative outcomes. Navigating these complexities, the study's implications extend beyond the mouse model, providing a foundation for understanding and intervening in the broader landscape of neurodegenerative diseases in humans.

  • Monocyte-derived macrophages accumulate in selected brain regions during healthy ageing excluding large areas of the frontal cortex.

  • Age-accumulating monocyte-derived macrophages acquire transcriptomic identities similar to YS-derived microglia including expression of the ‘signature microglia identity” gene Sall1.

  • The common clonal haemopoiesis variant Dnmt3aR822H impacts the global epigenome and transcriptome of monocyte-derived macrophages that seed the brain.

  • BM transplants compromising of HSC with Dnmt3aR822H leads to pathogenetic monocyte-derived macrophages that enter the brain and promote motor deficits resembling Parkinsonian disorders.


Limitations

  • To seed the CNS with MoMΦ derived from Dnmt3aR822H HSC, the authors engrafted Cx3cr1gfp/+ animals with BM of 10-month-old VavCre: hDNMT3AR822H mice, or age matched Cre-negative littermate BM as controls. However, it would have been interesting and made a stronger statement if the authors investigated if aged VavCre: Dnmt3aR822H also exhibit spontaneous age-associated accumulation of monocyte-derived macrophages in certain brain regions including the substantia nigra pars compacta, and if these mice also developed motor dysfunction. Also, it is not clear why 10-month-old mice were selected as 10 months is not regarded as ‘aged’ – rather age mice to 20-24 months where possible.

  • Although the authors show that there is broad transcriptional and epigenetic dysregulation in MoMacs that harbour Dnmt3aR822H, this is very descriptive referring to a ‘more activated’ state. More details on what pathways were affected in mutated cells would enhance our understanding of the effect of the mutation on these cells.

  • It would further contribute to the authors findings if they also showed that these cells react differentially to an age-related challenge for example LPS due to the epigenic reprogramming caused by the mutation.

  • Moreover, the validation of these findings in patient biopsies is necessary in understanding the relevance of the disease pathology and relation of mutated Dnmt3a in CH affecting brain pathologies through the MoMΦ seeding from clonal hematopoiesis.

It would further be interesting to know:

  • Why do monocyte-derived macrophages only seed selected areas of the brain during healthy ageing? What are the signals that direct this? Why is the cortex largely excluded for example?

  • Dnmt3aR822H is important in DNA methylation – what effect does this mutation have on the epigenetic profile of these monocyte-derived macrophages and their ability to respond to stimuli?


Significance/Novelty

This study first demonstrates that Dnmt3a mutations in clonal hematopoiesis can result in pathogenic macrophages seeding the brain and resulting in Parkinsonian-like deficits in mice. This provides a unique perspective on the relation between hematologic and neurological disorders that if validated in humans would bring insight into possible future treatment strategies.


Credit

Reviewed by Austeja Baleviciute as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.

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