A new fate mapping system reveals context-dependent random or clonal expansion of microglia

Tay, Tuan Leng; Mai, Dominic; Dautzenberg, Jana; Fernández-Klett, Francisco; Lin, Gen; Sagar,; Datta, Moumita; Drougard, Anne; Stempfl, Thomas; Ardura-Fabregat, Alberto; Staszewski, Ori; Margineanu, Anca; Sporbert, Anje; Steinmetz, Lars M.; Pospisilik, J. Andrew; Jung, Steffen; Priller, Josef; Grün, Dominic; Ronneberger, Olaf; Prinz, Marco

doi:10.1038/nn.4547

Cited by 484 publications

(516 citation statements)

References 51 publications

Supporting

Mentioning

489

Contrasting

Unclassified

Order By: Relevance

“…How this genetic 'memory' in activated microglia affects their function and neuropathic pain remains unknown, but will be important in future research because a recent study in the facial motor nucleus found that some microglia proliferated by PNI persist for approximately two months post-PNI. 34) In summary, our longitudinal and detailed analyses of SDH microgliosis after PNI further characterized a series of their activation. In particular, by using short-pulse labeling of proliferating cells, this study identified for the first time a narrow time window to induce a proliferation burst of SDH microglia after PNI.…”

Section: Discussionmentioning

confidence: 76%

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Kohno

Kitano

Kohro

et al. 2018

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Neuropathic pain, a highly debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. Previous studies have implicated activated microglia in the spinal dorsal horn (SDH) as key cellular intermediaries in neuropathic pain. Microgliosis is among the dramatic cellular alterations that occur in the SDH in models of neuropathic pain established by peripheral nerve injury (PNI), but detailed characterization of SDH microgliosis has yet to be realized. In the present study, we performed a short-pulse labeling of proliferating cells with ethynyldeoxyuridine (EdU), a marker of the cell cycle S-phase, and found that EdU microglia in the SDH were rarely observed 32 h after PNI, but rapidly increased to the peak level at 40 h post-PNI. Numerous EdU microglia persisted for the next 20 h (60 h post-PNI) and decreased to the baseline on day 7. These results demonstrate a narrow time window for rapidly inducing a proliferation burst of SDH microglia after PNI, and these temporally restricted kinetics of microglial proliferation may help identify the molecule that causes microglial activation in the SDH, which is crucial for understanding and managing neuropathic pain.Key words proliferation; microgliosis; spinal dorsal horn; neuropathic pain; peripheral nerve injury Neuropathic pain is a debilitating chronic pain state caused by damage to the nervous system incited by cancer, diabetes, chemotherapy and trauma. One of the hallmark symptoms is mechanical allodynia (non-nociceptive mechanical stimuli elicit pain), and neuropathic pain is often resistant to currently available therapies. 1) Injury to peripheral nerves of rodents, which are frequently used as models of neuropathic pain, produces mechanical pain hypersensitivity and alterations at molecular and cellular levels that result in multiple forms of neuronal plasticity and structural reorganization, not only in the affected sensory ganglion cell body, but also in the spinal dorsal horn (SDH). 2,3) The peripheral nerve injury (PNI)-induced alterations in the SDH are observed not only in neurons, but also in glial cells, especially microglia, which are known as resident immune cells in the central nervous system (CNS). Following PNI, SDH microglia become activated through a progressive series of changes in their morphology, expression of a variety of genes and cell number. 4) One of the most prominent features of microglial activation is an increase in the number of microglia (called microgliosis). Since PNI-induced microgliosis in the SDH was recorded in 1970s 5) and the rodent models of neuropathic pain were established in 1990s, 6-9) studies have investigated the mechanism for microgliosis in the SDH after PNI. Two possible mechanisms (proliferation of resident microglia 10,11) and infiltration of bone marrow-derived monocytes 12) ) have been considered, but it is now thought that local expansion of resident microglia by proliferation is the primary cellular basis for SDH microgliosis after PNI...

show abstract

Section: Discussionmentioning

confidence: 76%

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Kohno

Kitano

Kohro

et al. 2018

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…A recent investigation revealed that microglial cell number is tightly controlled by temporal and spatial coupling of apoptosis and proliferation within the microglial population, which provides evidence for tight control of microglial cell numbers (85). Using a novel microglia-fate mapping system, it was shown that in the healthy brain regional differences in microglia self-renewal exist and that microglia expansion is a random process during homeostasis that can shift to clonality upon pathology (86).…”

Section: Physiological Function Of Microglia In the Adult Brainmentioning

confidence: 99%

Microglia in steady state

Kierdorf¹,

Prinz²

2017

Journal of Clinical Investigation

Self Cite

230

179

View full text Add to dashboard Cite

“…For example, it remains unclear if the self-renewal of PVM takes place through brain-resident progenitors and, if so, the identity of these cells and their relationships to microglia and other brain-resident macrophage populations remain to be defined. Microglial turnover varies regionally and results from a stochastic cell division process in homeostatic conditions and from expansion of selected clones after local microglial proliferation caused by facial nerve transection [71]. It remains unclear if similar processes of self-renewal and expansion, independent of a precursor pool, also are involved in PVM turnover and proliferation.…”

Section: Future Directionsmentioning

confidence: 99%

Brain perivascular macrophages: characterization and functional roles in health and disease

et al. 2017

View full text Add to dashboard Cite

Perivascular macrophages (PVM) are a distinct population of resident brain macrophages characterized by a close association with the cerebral vasculature. PVM migrate from the yolk sac into the brain early in development and, like microglia, are likely to be a self-renewing cell population that, in the normal state, is not replenished by circulating monocytes. Increasing evidence implicates PVM in several disease processes, ranging from brain infections and immune activation to regulation of the hypothalamic-adrenal axis and neurovascular-neurocognitive dysfunction in the setting of hypertension, Alzheimer disease pathology, or obesity. These effects involve crosstalk between PVM and cerebral endothelial cells, interaction with circulating immune cells, and/or production of reactive oxygen species. Overall, the available evidence supports the idea that PVM are a key component of the brain-resident immune system with broad implications for the pathogenesis of major brain diseases. A better understanding of the biology and pathobiology of PVM may lead to new insights and therapeutic strategies for a wide variety of brain diseases.

show abstract

A new fate mapping system reveals context-dependent random or clonal expansion of microglia

Cited by 484 publications

References 51 publications

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents

Microglia in steady state

Brain perivascular macrophages: characterization and functional roles in health and disease

Contact Info

Product

Resources

About