Bone marrow-derived cells in the population of spinal microglia after peripheral nerve injury

Abstract

Accumulating evidence indicates that peripheral nerve injury (PNI) activates spinal microglia that are necessary for neuropathic pain. Recent studies using bone marrow (BM) chimeric mice have reported that after PNI, circulating BM-derived cells infiltrate into the spinal cord and differentiate into microglia-like cells. This raises the possibility that the population of spinal microglia after PNI may be heterogeneous. However, the infiltration of BM cells in the spinal cord remains controversial because of experimental adverse effects of strong irradiation used for generating BM chimeric mice. In this study, we evaluated the PNI-induced spinal infiltration of BM-derived cells not only by irradiation-induced myeloablation with various conditioning regimens, but also by parabiosis and mice with genetically labelled microglia, models without irradiation and BM transplantation. Results obtained from these independent approaches provide compelling evidence indicating little contribution of circulating BM-derived cells to the population of spinal microglia after PNI.

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

“…31,32) However, infiltration of circulating monocytes in the SDH, 12) which is reported to express Iba1, does not contribute to the PNI-induced SDH microgliosis, since recent studies using bone marrow chimeric mice subjected to mild irradiation, parabiosis mice and doubletransgenic mice (enable distinct visualization of resident microglia and circulating monocytes) demonstrated no evidence for the involvement of circulating monocytes. 4,10,11) Numerous microglia induced by PNI gradually returned to pre-PNI levels, the time-course of which is similar to a recovery of PNI-induced pain hypersensitivity. 23) Interestingly, SDH microglia still retained a significantly high cell number even about 2 months after the injury when pain hypersensitivity was fully recovered.…”

“…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. 4,10,11) However, in stark contrast to the characterization of temporal and spatial changes in the immunostaining levels of microglial markers (CD11b or ionized calcium-binding adapter molecule 1 (Iba1)) in the SDH that have so far been extensively studied, 4) the temporal kinetics of microglial proliferation after PNI have yet to be fully characterized.…”

“…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. 4,10,11) However, in stark contrast to the characterization of temporal and spatial changes in the immunostaining levels of microglial markers (CD11b or ionized calcium-binding adapter molecule 1 (Iba1)) in the SDH that have so far been extensively studied, 4) the temporal kinetics of microglial proliferation after PNI have yet to be fully characterized. While recent studies reported an involvement of colony-stimulating factor 1 (CSF1) expressed in injured dorsal root ganglion (DRG) neurons in the PNI-induced proliferation, 4,13,14) the expression of CSF1 in DRG neurons (and also its receptor CSF1R in microglia) is upregulated for a few weeks after PNI 13,14) when microglial proliferation has already terminated.…”

Recent advances in understanding neuropathic pain: glia, sex differences, and epigenetics

“…(ii) TMEM16F in microglia mediates their phagocytosis of GABAergic-interneuron terminals 17 . (iii) Whether monocytes infiltrate spinal cord and their relative role versus resident microglia are still unclear 22, 26, 28, 29, 32 . (iv) Upregulated connexin 43 in astrocytes triggers the secretion of CXCL1 to activate CXCR2 on DRG neuron central terminals and spinal interneurons 33 .…”

“…The exclusive role of resident spinal microglia was explored by Tashima et al , who proposed that irradiation and bone marrow transplantation, often employed in earlier studies, possibly impair the blood–spinal cord barrier, which represents an experimental artifact underlying monocyte/macrophage extravasation in the spinal cord 28 . This was supported by the absence of spinal cord infiltration by circulating monocytes by using less toxic irradiation protocols, parabiotic mice, and mice with genetically labeled microglia.…”