Bone marrow cell recruitment mediated by inducible nitric oxide synthase/stromal cell-derived factor-1alpha signaling repairs the acoustically damaged cochlear blood-labyrinth barrier.
Using a mouse model with noise-induced cochlear blood-labyrinth-barrier (CBLB) injury, we examined the effects of inducible nitric oxide synthase (iNOS) on the recruitment of bone marrow-derived cells (BMDCs) to the CBLB after acoustic injury. Lethally irradiated C57BL/6J and B6.129P2-Nos2(tm1Lau)/J mice were transplanted with GFP(+)-BMDCs from C57Bl/6-Tg (UBC GFP) mice. Four weeks after transplantation, we assessed the population of GFP(+)-BMDCs in the CBLB. Only small numbers of GFP(+)-BMDCs were found to infiltrate the area of the CBLB in the control recipient mice. However, robust GFP(+)-BMDC migration occurred in the area of the CBLB within the injured cochlea during the first week following acoustic trauma, and further BMDC accumulation was seen by 2 weeks posttrauma. After 4 weeks, the BMDCs were integrated into vessels. Local iNOS from perivascular resident macrophages was found to be important for BMDC infiltration, since mice deficient in iNOS (Inos(-/-)) and mice with iNOS that had been inhibited by 1400W displayed reduced BMDC infiltration. Stromal cell-derived factor-1α (SDF-1α) and its chemokine receptor 4 (CXCR4) were required for the iNOS-triggered recruitment. BMDC recruitment was significantly reduced by the inhibition of SDF-1α activity. Inhibition of the iNOS/SDF-1α signaling pathway reduced vascular repair as observed by reduced vascular density. Our study revealed an intrinsic signaling pathway of iNOS that mediates SDF-1α to promote GFP(+)-BMDC infiltration/targeting in cochlear vascular repair.
Oregon Hearing Research Center, Department of Otolaryngology and Head and Neck Surgery, Oregon Health and Science University, Portland, OR 97239, USA.
Min
M
Dai
Yue
Y
Yang
Irina
I
Omelchenko
Alfred L
AL
Nuttall
Allan
A
Kachelmeier
Ruijuan
R
Xiu
Xiaorui
X
Shi
D000162:Acoustics; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003051:Cochlea / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007758:Ear, Inner / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014945:Wound Healing / Q000235:genetics* / Q000502:physiology
D054377:Chemokine CXCL12; D052247:Nitric Oxide Synthase Type II