• Cell transplantation
• Intervertebral disc degeneration
• Progenitor cell
• Stem cell
• Stromal cell

• Intervertebral Disc Degeneration/surgery
• Humans
• Animals
• Stem Cell Transplantation
• Journal Impact Factor
• Bibliometrics

• molecular biology
• pathogenesis
• apoptosis

It has been reported that bone marrow mesenchymal stem cells (BMSCs) are a potential source of autologous stem cells to support the nucleus pulposus (NP) regeneration in intervertebral disc degeneration (IDD). Herein, we aim to study the mechanism underlying the effects of BMSC-derived extracellular vesicles (BMSC-EVs) on nucleus pulposus cells (NPCs) in IDD.

EVs were isolated from BMSCs. An IDD model was surgically established in C57BL/6J mice. NPCs were exposed to tBHP to establish an IDD cell model. RNA sequencing was performed to identify differentially expressed circRNAs in NP tissues harvested from mice with IDD. Interactions among circ_0050205, miR-665, and GPX4 were validated, and different interventions were used to study the roles of these molecules in NPC biological functions.

BMSC-EVs promoted NPC survival and inhibited NPC apoptosis and extracellular matrix (ECM) degradation. circ_0050205 expression was downregulated in the NP tissues of IDD mice, and BMSC-EVs facilitated NPC survival and suppressed ECM degradation in NPCs by transferring circ_0050205. circ_0050205 sponged miR-665 and upregulated GPX4 expression. BMSC-EVs expressing circ_0050205 promoted NPC survival-inhibited ECM degradation in NPCs and alleviated IDD in mice via the miR-665/GPX4 axis.

In conclusion, BMSC-EVs promoted NPC survival-inhibited ECM degradation in NPCs and attenuated IDD progression via the circ_0050205/miR-665/GPX4 axis.

• ADC mapping
• CEST
• MR spectroscopy
• T1ρ mapping
• T2 mapping
• diffusion-weighted MRI
• discogenic low back pain
• intervertebral disc degeneration
• q-space imaging
• sodium MRI

The etiology of lumbocrural pain is tightly concerned with intervertebral disk degeneration (IDD). Bone mesenchymal stem cell (BMSC)-based therapy bears potentials for IDD treatment. The properties of microRNA (miRNA)-modified BMSCs may be altered. This study investigated the role and mechanism of BMSCs promoting extracellular matrix (ECM) remodeling of degenerated nucleus pulposus cells (NPCs) via the miR-101-3p/EIF4G2 axis. NPCs were collected from patients with IDD and lumbar vertebral fracture (LVF). The expressions of miR-101-3p and ECM-related proteins, Collagen-I (Col-I) and Collagen-II (Col-II), were detected using the reverse transcription-quantitative polymerase chain reaction. The expressions of Col-I and Col-II, major non-collagenous component Aggrecan, and major catabolic factor Matrix metalloproteinase-13 (MMP-13) were detected using Western blotting. BMSCs were cocultured with degenerated NPCs from patients with IDD. Viability and apoptosis of NPCs were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. After the degenerated NPCs were transfected with the miR-101-3p inhibitor, the expressions of ECM-related proteins, cell viability, and apoptosis were detected. The targeting relationship between miR-101-3p and EIF4G2 was verified. Functional rescue experiments verified the effects of miR-101-3p and EIF4G2 on ECM remodeling of NPCs. Compared with the NPCs of patients with LVF, the degenerated NPCs of patients with IDD showed downregulated miR-101-3p, Col-II, and Aggrecan expressions and upregulated MMP-13 and Col-I expressions. BMSCs increased the expressions of miR-101-3p, Aggrecan, and Col-II, and decreased the expressions of MMP-13 and Col-I in degenerated NPCs. BMSCs enhanced NPC viability and repressed apoptosis. Downregulation of miR-101-3p suppressed the promoting effect of BMSCs on ECM remodeling. miR-101-3p targeted EIF4G2. Downregulation of EIF4G2 reversed the inhibiting effect of the miR-101-3p inhibitor on ECM remodeling. In conclusion, BMSCs increased the miR-101-3p expression in degenerated NPCs to target EIF4G2, thus promoting the ECM remodeling of NPCs.

• Collagen-I
• Collagen-II
• EIF4G2
• bone mesenchymal stem cells
• extracellular matrix remodeling
• intervertebral disc degeneration
• miR-101-3p
• nucleus pulposus cells

Intervertebral disk (IVD) degeneration is one of the most common musculoskeletal disease. Current clinical treatment paradigms for IVD degeneration cannot completely restore the structural and biomechanical functions of the IVD. Bio-therapeutic techniques focused on progenitor/stem cells, especially IVD progenitor cells, provide promising options for the treatment of IVD degeneration. Endogenous repair is an important self-repair mechanism in IVD that can allow the IVD to maintain a long-term homeostasis. The progenitor cells within IVD play a significant role in IVD endogenous repair. Improving the adverse microenvironment in degenerative IVD and promoting progenitor cell migration might be important strategies for implementation of the modulation of endogenous repair of IVD. Here, we not only reviewed the research status of treatment of degenerative IVD based on IVD progenitor cells, but also emphasized the concept of endogenous repair of IVD and discussed the potential new research direction of IVD endogenous repair.

• endogenous repair strategy
• intercellular communication
• intervertebral disk – degeneration
• microenvironment
• progenitor/stem cell

Purpose: In the degenerated intervertebral disc (IVD), matrix acidity challenges transplanted bone marrow mesenchymal stem cells (BMSCs). The Ca²⁺-permeable acid-sensing ion channel 1a (ASIC1a) is responsible for acidosis-mediated tissue injury. The aim of our study was to confirm whether ASIC1a activation induces BMSC apoptosis under conditions that mimic the acidic microenvironment of the degenerated IVD.

Methods: ASIC1a expression in rat BMSCs was investigated by real time-PCR, Western blot (WB) and immunofluorescence. The proliferation and apoptosis of BMSCs under acidic conditions were analyzed by MTT and TUNEL assays. Ca²⁺-imaging was used to assess the acid-induced increase in the intracellular Ca²⁺ concentration ([Ca²⁺]i). The activation of calpain and calcineurin was analyzed using specific kits, and WB analysis was performed to detect apoptosis-related proteins. Ultrastructural changes in BMSCs were observed using transmission electron microscopy (TEM).

Results: Acid exposure led to the activation of ASIC1a and increased BMSC apoptosis. The Ca²⁺ imaging assay showed a significant increase in the [Ca²⁺]i in response to a solution at pH 6.0. However, BMSC apoptosis and [Ca²⁺]i elevation were alleviated in the presence of an ASIC1a inhibitor. Moreover, ASIC1a mediated the Ca²⁺ influx-induced activation of calpain and calcineurin in BMSCs. WB analysis and TEM revealed mitochondrial apoptosis, which was inhibited by an ASIC1a inhibitor, in BMSCs under acidic conditions.

Conclusions: The mimical acidic microenvironment of the degenerated IVD can induce BMSC apoptosis by activating Ca²⁺-permeable ASIC1a. An acid-induced elevation of [Ca²⁺]i in BMSCs leads to the subsequent activation of calpain and calcineurin, further resulting in increased mitochondrial permeability and mitochondrial-mediated apoptosis.

• Acid-sensing ion channel 1a
• Apoptosis
• Bone marrow mesenchymal stem cells
• Intervertebral disc degeneration

Low back pain has become more prevalent in recent years, causing enormous economic burden for society and government. Common therapies used in clinics including conservative treatment and surgery can only relieve pain. Subsequent cell-based treatment such as mesenchymal stem cell transplantation poses problems such as short duration of therapeutic effect and tumorigenesis. Recently, the discovery and identification of stem cell niche and stem/progenitor cells in intervertebral disc bring increased attention to endogenous repair strategy. Therefore, we review the studies involving endogenous repair strategy and present the characteristics and current status of this treatment. Meanwhile, we also discuss the strategy and perspective of endogenous repair strategy in future.

• Low back pain
• Intervertebral disc degeneration
• Stem cell niche
• Stem/progenitor cell
• Endogenous repair strategy
• Stem cell treatment

• Stem cell
• adhesion makers
• intervertebral disc degeneration
• menopause
• neurogenesis
• senescence.

• Biomaterials, chemokines
• Disc degenerative disease
• Drug delivery systems
• Growth factors
• Low back pain
• Progenitor cells
• Regenerative medicine
• Stem cells
• miRNA

• Animals
• Cell- and Tissue-Based Therapy
• Humans
• Intervertebral Disc Degeneration/metabolism
• Intervertebral Disc Degeneration/therapy
• Mesenchymal Stem Cell Transplantation
• Regeneration

• Cytoplasmic Vacuole
• Embryogenesis
• Intervertebral Disk
• Notochord
• Sclerotome

The objective of this study was to investigate the curative effects of mesenchymal stem cells' tenogenic differentiation on linea alba incision healing induced by bone morphogenetic protein-12. Mesenchymal stem cells were isolated and induced by 10 ng/ml of bone morphogenetic protein-12 for 48 h. Expression of scleraxis, collagen I and collagen III were examined at 48 h, 5 and 7 days to investigate the tenogenic differentiation. The expression of scleraxis increases continually even in the absence of bone morphogenetic protein-12 for 5 days (P<0.01). The expression of collagen I and III requires persistent inducing. Then fifty Sprague-Dawley rats were randomly divided into five groups: negative control, positive control, sham group, native mesenchymal stem cells and tenogenically differentiated mesenchymal stem cells. Tensiometric testing and modified semiquantitative histological analysis were performed to explore the curative effects. The tension levels in the positive control, sham, native mesenchymal stem cells and tenogenically differentiated mesenchymal stem cells were 44, 41.8, 51.6 and 69.7%, respectively, compared with the negative control. Tenogenically differentiated mesenchymal stem cells exhibited a greater increase in tension compared with positive control, sham and native mesenchymal stem cell groups (P<0.05). From the sections stained with Masson's Trichrome, collagen organization and amount of tenogenically differentiated mesenchymal stem cells was better than the other three groups (P<0.05). In conclusion, mesenchymal stem cells' tenogenic differentiation induced by bone morphogenetic protein-12 can enhance linea alba incision healing.

• bone morphogenetic protein-12
• incisional hernia
• linea alba incision
• mesenchymal stem cells

• Degenerated intervertebral disc
• Differentiation
• Nucleus pulposus progenitor/stem cells
• Phenotypic markers
• Proliferation capacity

• IL-1β
• MACT
• MRI
• chondrocytes
• matrix
• transplantation

Magnetic resonance imaging (MRI) is a useful non-invasive tool for evaluating abnormalities of intervertebral discs. However, there are few studies which applied functional MRI techniques to investigate degenerative changes in cervical and cervicothoracic junction (CTJ) spine among adults. The aim of this study was to compare T2 relaxation time measurement evaluation with morphological grading for assessing cervical and CTJ intervertebral discs (IVD) in the patients suffering neck, shoulder, and upper back pain.

Sixty-three patients (378 IVDs) and 60 asymptomatic volunteers (360 IVDs) of the cervical and CTJ discs were assessed using a 3.0 T magnetic resonance imaging (MRI) protocol, including an sagittal T2 relaxation time protocol. The relaxation time values of the nucleus pulposus (NP) were recorded and all discs were visually graded according to Pfirrman’s grading system. The correlation between T2 relaxation time values and qualitative clinical grading of degeneration, patient age, sex and anatomic level were analyzed

There is a clear trend of decreasing mean T2 values of the NP associate with increasing Pfirrmann grades (C2-T1) for both patients and asymptotic volunteers. Significant T2 differences were seen among grades I-V (P < 0.05). However, grade V was not observed in the CTJ. Linear correlation analysis revealed a strong negative association between T2 values of the NP and Pfirrmann grade (r = −0.588, r = −0.808) of C2-7 and C7T1. Age were also significantly correlated NP T2 values (r = −0.525, r = −0.723) for patients and volunteers. Moreover, the receiver operating characteristic analysis for average measures in a range from 0.70-0.79 (C2-7) to 0.84-0.89 (C7T1) for patients.

T2 quantitation provides a more sensitive and robust approach for detecting and characterizing the early stage of IVD degeneration and age-associated disc changes.

The online version of this article (doi:10.1186/s12880-017-0182-z) contains supplementary material, which is available to authorized users.

• Cervical
• Cervicothoracic Junction
• Intervertebral Disc Degeneration
• Magnetic Resonance Imaging
• T2 Relaxation Time

• MAPK
• NF-κB
• TGF-β1
• intervertebral disc
• paracrine

This study provides experimental results on the applicability of bone marrow mesenchymal stem cells (BMSCs) for the repair of intervertebral disc annulus fibrosus in rabbits.

Thirty healthy rabbits were randomized into an observation group (n=15) and a control group (n=15). Both groups underwent degeneration of intervertebral disc annulus fibrosus. The observation group was treated with a solution of BMSCs and dexamethasone sodium phosphate, while the control group was treated with dexamethasone sodium phosphate only.

The two groups were compared for efficacy and pathological conditions after treatment. Both disc height index and level of type II collagen in nucleus pulposus were significantly higher in the observation group than in the control group at 2, 4, 8, and 12 weeks after degeneration (p<0.05 for all comparisons). The percentages of grade 0 and grade 1 were significantly higher in the observation group than in the control group (p<0.05 for both grade 0 and 1 comparisons), while the percentage of grade 4 and grade 5 were significantly lower in the observation group than in the control group (p<0.05 for both grade 4 and 5 comparisons).

BMSCs cultured in vitro can effectively repair intervertebral disc annulus fibrosus, which is of positive significance, and thus is clinically recommended.

Intervertebral disc (IVD) degeneration is characterized by significant biochemical and histomorphological alterations, such as loss of extracellular matrix (ECM) integrity, by abnormal synthesis of ECM main components, resultant from altered anabolic/catabolic cell activities and cell death. Mesenchymal Stem/Stromal Cell (MSC) migration towards degenerated IVD may represent a viable strategy to promote tissue repair/regeneration. Here, human MSCs (hMSCs) were seeded on top of cartilaginous endplates (CEP) of nucleotomized IVDs of bovine origin and cultured ex vivo up to 3 weeks. hMSCs migrated from CEP towards the lesion area and significantly increased expression of collagen type II and aggrecan in IVD, namely in the nucleus pulposus. Concomitantly, hMSCs stimulated the production of growth factors, promoters of ECM synthesis, such as fibroblast growth factor 6 (FGF-6) and 7 (FGF-7), platelet-derived growth factor receptor (PDGF-R), granulocyte-macrophage colony-stimulating factor (GM-CSF) and insulin-like growth factor 1 receptor (IGF-1sR). Overall, our results demonstrate that CEP can be an alternative route to MSC-based therapies for IVD regeneration through ECM remodeling, thus opening new perspectives on endogenous repair capacity through MSC recruitment.

Intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible treatments. Indeed, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers (e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell-based therapy for disc regeneration.

• Stem cells
• Intervertebral disc degeneration
• Spine
• Tissue engineering
• Cell therapy

To evaluate T2 relaxation time change using axial T2 mapping in a rabbit degenerated disc model and determine the most correlated variable with histologic score among T2 relaxation time, disc height index, and Pfirrmann grade.

Degenerated disc model was made in 4 lumbar discs of 11 rabbits (n = 44) by percutaneous annular puncture with various severities of an injury. Lumbar spine lateral radiograph, MR T2 sagittal scan and MR axial T2 mapping were obtained at baseline and 2 weeks and 4 weeks after the injury in 7 rabbits and at baseline and 2 weeks, 4 weeks, and 6 weeks after the injury in 4 rabbits. Generalized estimating equations were used for a longitudinal analysis of changes in T2 relaxation time in degenerated disc model. T2 relaxation time, disc height index and Pfirrmann grade were correlated with the histologic scoring of disc degeneration using Spearman's rho test.

There was a significant difference in T2 relaxation time between uninjured and injured discs after annular puncture. Progressive decrease in T2 relaxation time was observed in injured discs throughout the study period. Lower T2 relaxation time was observed in the more severely injured discs. T2 relaxation time showed the strongest inverse correlation with the histologic score among the variables investigated (r = -0.811, p < 0.001).

T2 relaxation time measured with axial T2 mapping in degenerated discs is a potential method to assess disc degeneration.

• Degeneration
• Intervertebral disc
• MRI
• Rabbit
• T2 mapping

• Cell differentiation
• Cellular immunophenotype
• Intervertebral disc
• Mesenchymal stem cells
• Stem cell niches

• Animal trial
• Intervertebral disc
• Regeneration
• Stem cell therapy
• Systematic review

• Animals
• Disease Models, Animal
• Humans
• Intervertebral Disc/physiopathology
• Intervertebral Disc Degeneration/therapy
• Regeneration
• Stem Cell Transplantation
• Treatment Outcome