Single-cell atlas unveils cellular heterogeneity and novel markers in human neonatal and adult intervertebral discs

Jiang, Wensen; Glaeser, Juliane D.; Salehi, Khosrowdad; Kaneda, Giselle; Mathkar, Pranav; Wagner, Anton; Ho, Ritchie; Sheyn, Dmitriy

doi:10.1016/j.isci.2022.104504

Cited by 19 publications

(24 citation statements)

References 67 publications

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“…These capabilities are due to the complex interaction between two morphologically, biomechanically, and biochemically distinct tissues: the annulus fibrosus (AF) and the nucleus pulposus (NP). Two cell types of different developmental origins primarily compose the IVD, chondrocyte-like cells within the nucleus pulposus and the inner annulus fibrosis, and fibroblast-like cells within the outer AF; however, single-cell RNA sequencing studies suggest additional cellular heterogeneity and the potential for IVD progenitor cells within model organisms [ 7 , 8 , 9 ]. The AF consists of highly organized concentric rings (lamellae) of fibrocartilaginous material that surround the NP.…”

Section: Introductionmentioning

confidence: 99%

Macrophages and Intervertebral Disc Degeneration

Koroth

Buko

Abbott

et al. 2023

IJMS

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The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

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Section: Introductionmentioning

confidence: 99%

Macrophages and Intervertebral Disc Degeneration

Koroth

Buko

Abbott

et al. 2023

IJMS

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“…This hypothesis is consistent with a study by Richardson et al which showcased that degenerating human NPCs can induce neurite outgrowth in vitro ( 35 ). Here we extended these results by testing this phenomenon in vivo and by addressing the heterogeneity of NPC populations ( 35 ) as suggested by other studies ( 33, 40, 41 ).…”

Section: Discussionmentioning

confidence: 60%

“…Previous NPC-focused studies mostly considered the anabolic function of NPCs (expression of proteoglycan and collagen markers such as ACAN and COL2Al) ( 31, 72, 73 ) rather than pain induction. Also, the precise identification of the pain subtype among NPC population was only made possible in recent years following the advent of scRNA-seq technology ( 40, 41, 74 ). The NPC-mediated pain mechanism reported in the present study should be further investigated and leveraged for NPC-focused cell therapies.…”

Section: Discussionmentioning

confidence: 99%

“…Single-cell RNA sequencing (scRNA-seq) technology can be used to determine cell subtypes, identify rare cell populations, and discover novel biological markers of IVD cells ( 40–42 ). ScRNA-seq technology could establish mechanisms of discogenic LBP specific to NPC sub-populations.…”

Section: Introductionmentioning

confidence: 99%

“…ScRNA-seq technology could establish mechanisms of discogenic LBP specific to NPC sub-populations. For example, there was limited understanding of the divergent NPC subtypes ( 33 ) until single-cell technologies led to the discovery of heterogeneous populations of cells residing in the IVD ( 40–42 ). The present study investigates the role of NPC subtypes in mediating discogenic LBP by leveraging scRNA-seq of patient-derived cells and validates the findings in both in vitro and in vivo models of discogenic pain.…”

Section: Introductionmentioning

confidence: 99%

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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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Spatiotemporal Characterization of Human Early Intervertebral Disc Formation at Single‐Cell Resolution

et al. 2023

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The intervertebral disc (IVD) acts as a fibrocartilaginous joint to anchor adjacent vertebrae. Although several studies have demonstrated the cellular heterogeneity of adult mature IVDs, a single‐cell transcriptomic atlas mapping early IVD formation is still lacking. Here, the authors generate a spatiotemporal and single cell‐based transcriptomic atlas of human IVD formation at the embryonic stage and a comparative mouse transcript landscape. They identify two novel human notochord (NC)/nucleus pulposus (NP) clusters, SRY‐box transcription factor 10 (SOX10)+ and cathepsin K (CTSK)+, that are distributed in the early and late stages of IVD formation and they are validated by lineage tracing experiments in mice. Matrisome NC/NP clusters, T‐box transcription factor T (TBXT)+ and CTSK+, are responsible for the extracellular matrix homeostasis. The IVD atlas suggests that a subcluster of the vertebral chondrocyte subcluster might give rise to an inner annulus fibrosus of chondrogenic origin, while the fibroblastic outer annulus fibrosus preferentially expresseds transgelin and fibromodulin . Through analyzing intercellular crosstalk, the authors further find that notochordal secreted phosphoprotein 1 (SPP1) is a novel cue in the IVD microenvironment, and it is associated with IVD development and degeneration. In conclusion, the single‐cell transcriptomic atlas will be leveraged to develop preventative and regenerative strategies for IVD degeneration.

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Single-cell atlas unveils cellular heterogeneity and novel markers in human neonatal and adult intervertebral discs

Cited by 19 publications

References 67 publications

Macrophages and Intervertebral Disc Degeneration

Macrophages and Intervertebral Disc Degeneration

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

Spatiotemporal Characterization of Human Early Intervertebral Disc Formation at Single‐Cell Resolution

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