Exploring the neurogenic differentiation of human dental pulp stem cells

Al-Maswary, Arwa A.; O’Reilly, Molly; Holmes, Andrew P.; Walmsley, Anthony D.; Cooper, Paul R.; Scheven, Ben A.

doi:10.1371/journal.pone.0277134

Cited by 21 publications

(16 citation statements)

References 145 publications

(178 reference statements)

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“…4F). To further identify axons, we examined the immunofluorescence staining of the neuron marker TUBB3 ( 73 , 74 ) and sensory neural marker Brn3a. We found that both markers were almost absent in the control NPCs but were strongly expressed by the iPSC-derived nociceptor-like sensory neurons (Fig.…”

Section: Resultsmentioning

confidence: 99%

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats

Jiang,

Glaeser,

Kaneda

et al. 2023

Sci. Transl. Med.

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Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.

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Section: Resultsmentioning

confidence: 99%

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats

Jiang,

Glaeser,

Kaneda

et al. 2023

Sci. Transl. Med.

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show abstract

“…We examined the immunofluorescence staining of neuron marker TUBB3 ( 62, 63 ) and sensory neural marker Brn3a. We found that both markers were almost absent in the nsNPCs but were strongly expressed by the iNOCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Jiang

Glaeser

Kaneda

et al. 2023

Preprint

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Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCsin vitro. The recreated pain phenotype activated functional sensory neurons responsein vitroand induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVDin vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP.One Sentence SummaryDiscogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs

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“…Although DP-SCs are very similar to mesenchymal stem cells, they differ from them by their expression of neuronal specific markers (10). Interestingly, the Ocrelizumab positively affect the neuronal differentiation as it was for the osteogenic and chondrogenic differentiations.In DP-SCs, it was shown that ERK/MAPK is necessary for neuronal differentiation (16). In another study, the MAPK and TGF-β signaling pathways were shown to play a central role in the neurogenic differentiation, and the difference in those pathways between the DP-SCs and MSCs make DP-SCs more potential to differentiate neuron-like cells (17).The enhanced MAPK and TGF-β signaling in DP-SCs might be the reason for being the target of Ocrelizumab.…”

Section: Discussionmentioning

confidence: 99%

Effects of Ocrelizumab on Dental Pulp Derived Mesenchymal Stem Cells

-¹,

-²

2022

IJFMR

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Multiple sclerosis (MS) is a chronic autoimmune central nervous system (CNS) disease characterized by inflammation, demyelination and axonal damage. The most important goal in MS treatment is to provide neuroregeneration. However, current treatments only work to slow the progression of MS. Ocrelizumab is a humanized anti-CD20 monoclonal antibody used in the treatment of MS. In this study, it was aimed to investigate the effects of Ocrelizumab on the proliferation and differentiation potential of dental pulp-derived stem cells (DP-SC). For this purpose, three different (1.5 µg/mL, 15 µg/mL and 150 µg/mL) doses of Ocrelizumab were added to the normal culture medium, and then proliferation analyzes at 24, 48 and 72 hours were performed with the WST-1 assay. Ocrelizumab treatment for 24 and 48 hours was observed to dose-dependently reduce the proliferation of stem cells. At 72 hours, the efficacy of the drug on proliferation was lost at low doses. Similarly, a dose-dependent decrease in the expression of stemness marker, Rex1, was detected. The expression of the adipogenic differentiation marker ADFP, osteogenic differentiation marker RUNX2, chondrogenic differentiation marker SOX9, and neurogenic differentiation marker TUBB3 were evaluated to determine the influence on the differentiation potential of stem cells under the drug effect. While RUNX2, SOX9 and TUBB3 expressions increased in a dose-dependent manner, there was a decrease in ADFP expression in parallel to the drug dose. According to the results of the study, ocrelizumab might have the potential to support the regenerative effects by supporting the differentiation of DP-SCs in osteogenic, chodrogenic and neurogenic.

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Exploring the neurogenic differentiation of human dental pulp stem cells

Cited by 21 publications

References 145 publications

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Effects of Ocrelizumab on Dental Pulp Derived Mesenchymal Stem Cells

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