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Bulk RNA-seq of human nucleusus pulposus from disc-degenerated patients

ABSTRACT: Failure of the nucleus pulposus (NP) causes intervertebral disc (IVD) disease and associated low-back pain, which are highly prevalent among the aged populations. Molecular and cellular changes underpinning the structural failures in age-associated IVD diseases (IDDs) remain poorly elucidated. Here, we first identified that TAGLN, which encodes the cytoskeleton regulator transgelin, was transcribed in healthy NPs of both human and mouse, but diminished with ageing. Immunostaining showed that TAGLN were expressed on the peripheral of mouse NP (periNP). Lineage analyses in Tagln-CreERT2 mice showed that NP cells were derived from Tagln+ cells in the periNP. The PeriNP cells were proliferative and can differentiate into the inner NP (innerNP). These Tagln+ cells and their descendants diminish with ageing or puncture-induced degeneration. Single-cell transcriptomics from neonatal and adult Tagln-CreERT2 IVDs confirmed that Tagln descendants uniquely populate the NP, wherein four sub-populations were identified: chondrocyte-like, Cd228+, Tagln+ and Car3+. Immunostaining confirmed Car3 expressed in innerNP. Computational analysis indicated the lineage trajectory from Tagln+ to Car3+ sub-population, along with the involvement of Fos/Jun/TGFβ cascades and partial epithelial-to-mesenchymal transition process. Removal of TGFβ mediator Smad4 by notochord specific Foxa2mNE-Cre resulted in decreased Tagln+ cells and abnormal disc morphology, resembling disc degeneration. Our study generates a single-cell transcriptomic atlas for healthy IVD, identifies Tagln+ PeriNP cells as a progenitor pool crucial for the IVD homeostasis, and provides potential targets for regenerative cell therapy against IVD degeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201396 | GEO | 2024/05/14

REPOSITORIES: GEO

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Tagln+ progenitors contribute to the development and maintenance of nucleus pulposus

Project description:Failure of intervertebral disc components, e.g. the nucleus pulposus causes intervertebral disc disease and associated low-back pain. Despite the high prevalence of disc disease, the changes in intervertebral disc cells and their regenerative potential with ageing and degeneration are not fully elucidated. Understanding the cell lineage, cell differentiation and maintenance of nucleus pulposus may have therapeutic application for the regeneration of degenerative disc, with significant impact for healthy ageing. Here we found that TAGLN expressing cells are present in human healthy nucleus pulposus, but diminish in degenerative disc. By lineage analyses in mice, we found cells in the nucleus pulposus are derived from a peripherally located population of notochord-derived Tagln expressing cells (PeriNP cells). The PeriNP cells are proliferative and can differentiate into the inner part of the nucleus pulposus. The Tagln+ cells and descendants diminish during aging and puncture induced disc degeneration. The maintenance and differentiation of PeriNP cells is partially regulated by Smad4 dependent signaling. Removal of Smad4 by nucleus pulposus specific Cre (Foxa2mNE-Cre), results in decreased Tagln+ cells and abnormal disc morphology, leading to disc degeneration. Our findings propose that the PeriNP Tagln expressing cells are a pool of notochord-derived progenitors that are important for maintenance of the nucleus pulposus and provide insights for regenerative therapy against intervertebral disc degeneration.

2024-05-14 | GSE186549 | GEO

Matrisome remodelling during Intervertebral Disc development and ageing

Project description:Intervertebral disc (IVD) degeneration is often the cause of low back pain. Degeneration occurs with age and is accompanied by extracellular matrix (ECM) depletion, culminating in nucleus pulpous (NP) extrusion and IVD destruction. The changes that occur in the disc with age have been under investigation. However, a thorough study of ECM remodelling is needed, to better understand IVD development and age-associated degeneration. As so, iTRAQ LC-MS/MS analysis of foetus, young and old bovine NPs, was used to define the NP matrisome. The enrichment of Collagen XII and XIV in foetus, Fibronectin and Prolargin in elder samples and Collagen XI in young ones was independently validated. This study provides the first matrisome database of healthy discs during development and ageing, which is key to determine the pathways and processes that maintain disc homeostasis. The factors identified may help to explain age-associated IVD degeneration or constitute putative effectors for disc regeneration.

2017-09-25 | PXD005616 | Pride

Matrisome remodelling during Intervertebral Disc development and ageing

Project description:Intervertebral disc (IVD) is often the cause of low back pain. Degeneration occurs with age and is accompanied by extracellular matrix (ECM) depletion, culminating in nucleus pulpous (NP) extrusion and IVD destruction. Although the changes that occur with ageing in the IVD have been under study, not much attention has been given to ECM remodelling during normal development. Therefore, a thorough study of ECM composition and a comprehensive view on how this microenvironment is affected in normal ageing conditions is needed, to better understand the processes involved in IVD development and in age-associated degeneration. We have compared the NP matrisome of bovine IVDs from foetus, young and old animals by quantitative iTRAQ LC-MS/MS. Protein expression levels of the most interesting candidates were validated by Western Blot analysis. In total, 161 bovine proteins were identified. Of these, 77 molecules were common to the three different age groups, of which 36 defined the NP matrisome. Differential expression levels obtained for Collagen Type XI, XII, XIV, Fibronectin and Prolargin were independently confirmed. Herein, we demonstrate a shift in NP matrisome signatures that occurs in healthy bovine IVDs with development and ageing. Thus, this study provides insight into factors that may explain age-associated IVD degeneration, and which are putative targets for therapy. It also highlights key molecules, characteristic of early developmental stages, which constitute potential effectors in IVD regeneration.

2017-09-25 | PXD004922 | Pride

IVD transcriptome with age

Project description:This study sought to elucidate the transcriptomic changes in the murine nucleus pulposus (NP) with age. These findings will contribute to the understanding of murine intervertebral disc (IVD) aging and degeneration.

2019-06-05 | GSE132182 | GEO

Genome-wide DNA methylation profile analysis of human intervertebral disc degeneration

Project description:The pathophysiology of intervertebral disc (IVD) degeneration is not entirely understood; however, environmental and endogenous factors under genetic predisposition are considered to initiate the degenerative changes of human IVDs. Aberrant epigenetic alterations play a pivotal role in several diseases, including osteoarthritis. However, epigenetic alternations, including DNA methylation, in IVD degeneration have not been evaluated. The purpose of this study was to comprehensively compare the genome-wide DNA methylation profiles of human IVD tissues, specifically nucleus pulpous (NP) tissues, with early and advanced stages of disc degeneration. We conducted, for the first time, a genome-wide DNA methylation profile comparative study and observed significant differences in DNA methylation profiles between early and advanced stages of human IVD degeneration. The overview of the DNA methylation profile in the current study revealed that differentially methylated loci were identified in many genes associated with known molecules that have been reported to be relevant to IVD degeneration. Importantly, changes in DNA methylation profiles were also found in genes that regulate the major signaling pathways, such as NF-κB, MAPK, and Wnt signaling, that are well known to be responsible for the pathogenesis of human disc degeneration.

2019-10-01 | GSE129789 | GEO

Dissecting inflammatory response in intervertebral disc degeneration: triggering of CD44 by IL-1beta

Project description:Objectives/Design: Intervertebral Disc (IVD) degeneration has been associated with a chronic inflammatory response, but knowledge on the contribution of distinct IVD cells, namely CD44, to the progression of IVD degeneration remains elusive. Material: Bovine nucleus pulposus (NP) cells. Treatment: Stimulation with IL-1beta (10ng/ml). Methods: CD44 NP cells were sorted and compared by gene expression and proteomics with the negative counterpart. Dynamics of CD44 gene and protein expression was analyzed upon pro-inflammatory treatment. Results: CD44 has a multidimensional functional role in IVD metabolism, ECM synthesis and production of neuropermissive factors. CD44 widespread expression in NP has been partially associated with CD14 and CD45, resulting in the identification of distinct cell subsets. Conclusions: This study points out CD44 and CD44-based cell subsets as relevant targets in the modulation of the IVD pro-inflammatory/degenerative cascade.

2024-05-22 | PXD048373 | Pride

In vitro differentiation of pluripotent stem cells towards notochordal-like cells

Project description:Description: The intervertebral disc (IVD) is a joint in the spine that is comprised of three major structures, the nucleus pulposus (NP), annulus fibrosus (AF) and cartilaginous endplate (EP). The NP is a proteoglycan-rich structure which contains a heterogenous population including the presence of progenitors such as the notochordal-like cells (NLCs) and NP cells, which are responsible for the synthesis and turnover of extracellular matrix in the NP. During aging and degeneration, there is a loss of cells, hydration, and changes in the ECM, that leads to the alterations in the biomechanical function of the IVD. The replenishment of cells, in particular, the progenitors are a potential therapy for IVD degeneration. However, a major challenge lies in obtaining sufficient numbers of healthy cells for treatment. This study used a 3 part protocol to differentiate pluripotent stem cells into NLCs in vitro.

2023-11-11 | GSE237546 | GEO

Actively synthesised proteins in human intervertebral disc

Project description:The intervertebral disc (IVD) is a joint in the spine that facilitates daily movement, comprising of the central nucleus pulposus (NP), surrounded by the annulus fibrosus (AF) and sandwiched between two cartilage endplates that function together as a unit. Changes to the IVD occur with aging, most drastically in the NP where it experiences dehydration and loss of cellularity, directly impacting on the integrity of the biomechanical functions of the IVD. Whilst the static proteome reflects the long-term accumulation of proteins and their turnover over the lifetime of the IVD, this information may not reflect immediate cellular changes that may alter during the course of time. To gain a better understanding of cellular function and protein turnover in disc homeostasis (health) versus aging, we analysed the actively synthesized proteins using the SILAC approach. Clinical specimens from spine surgeries for scoliosis (young samples; NP n=2, AF n=4) or degeneration (aged samples; NP n=1, AF n=1) were used in this study.

2021-01-29 | PXD018193 | Pride

Characterisation of the molecular signature of an 8 week-old human embryonic notochord

Project description:During embryonic development, the notochord is the precursor to the nucleus pulposus (NP) in the intervertebral disc (IVD), where the notochord cells differentiate to become notochordal-like cells in the NP, and are considered as potential progenitor cells to support the function of the NP. With aging and degeneration, there is a loss of these cells from the NP which ultimately affects IVD function. The characterisation of the molecular signature of the 8 week-old (gestational age) human embryonic notochord is a valuable resource to better understand the development from the notochord to the NP progenitors and as a benchmark for comparison to other datasets.

2023-11-11 | GSE237542 | GEO

Gene expression data for human intervertebral discs

Project description:The human intervertebral disc (IVD) is a complex and dynamic structure that functions to provide spinal stability, mobility and flexibility. It comprises three main compartments: 1) a water-rich central compartment called the nucleus pulposus (NP), which is enveloped by 2) the annulus fibrosus (AF) and sandwiched between 3) two cartilaginous endplates (EP) from which the IVD gains its nutrition and provides a means to get rid of metabolic waste. The IVD is constantly under extreme conditions of hypoxia, nutrition, and loading stresses. As such, it wears with ageing, and the rates of wearing may be sped up by a multitude of risk factors. Phenotypically, the AF may become weaker that a portion of it may protrude into neighboring tissues, resulting in disc bulging, or even worse, it may rupture and form a herniation Most striking of all, magnetic nuclear imaging (MRI) of the NP may become darker, with spotted high-intensity zones (HIZs), indications of dehydration and annular disruptions (Peng, et al. 2006). In a herniated or even collapsed disc, the contents of NP may leak into the neighboring spaces and external cells (such as macrophages) may infiltrate into the NP (Nakazawa, et al. 2018), causing the disc functions to be partially or fully compromised. The underlying mechanism of these involves complex interplays of cellular and molecular changes and remains poorly understood; nevertheless, the process is suggested to be triggered and driven by both environmental and genetic factors, or their combinations. In an effort to study the molecular dynamics of the ageing process of the human IVD, we profiled the transcriptomes of two groups of individuals: a young and non-degenerated group (N=2) and an aged and degenerated group (N=2). We profiled the transcriptomes of both AF and NP for each individual.

2020-06-30 | GSE147383 | GEO

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