Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies☆
Graphical abstract
Introduction
Low back pain (LBP) is a major public health concern. Approximately 650 million people are currently affected in the world and its socio-economic cost is increasing with population aging [[1], [2], [3]]. In the United States of America, the annual cost of chronic LBP exceeds $30 billion, which is in excess of the combined cost of stroke, respiratory infection, diabetes, coronary artery disease, and rheumatoid disease [[4], [5], [6]]. Moreover, LBP is the second most frequent cause for hospital visits and the leading cause of years lived with disability (the prevalence of a disorder multiplied by the short- or long-term loss of health associated with that disability) [7].
LBP is frequently associated (~40%) with intervertebral disc degenerative disease (DDD) and is commonly named discogenic lombalgia [8]. Intervertebral discs (IVD) are fibrocartilaginous tissues connecting the vertebral bodies. IVD are important to spinal function as they provide stability between vertebrae while permitting motion. The central part of the IVD, the Nucleus pulposus (NP), forms the hydrogel-like core of IVD. NP is primarily composed of proteoglycans and type II collagen fibers and its elastic function distributes hydraulic pressure in all directions within each IVD. NP is surrounded by the peripheral Annulus fibrosus (AF). The structure of the AF is characterized by concentrically arranged lamellae composed of type I and type II collagen fibers, as well as elastin fibers, which help withstand compressive forces and hold the NP in place during compression. Finally, NP and AF are sandwiched by the cartilaginous endplates (CEP). The CEP is a hyaline cartilaginous tissue that joins IVD with the adjacent bony vertebrae, ultimately providing intervertebral joints with functional continuity. DDD commonly involves changes in the IVD morphology as a result of the qualitative and quantitative alteration of the extracellular matrix (ECM) composition and a loss of resident NP cells. It is well established that a young and healthy NP tissue contains both nucleopulpocytes (NPCy; formerly named chondrocyte-like cells), mostly involved in ECM synthesis, and notochordal cells (NTC), which are known to play a pivotal role in IVD development, growth, and homeostasis (Fig. 1). The decrease in resident NP cell number is likely to be one of the initiating events of IVD degeneration. As a consequence, the balance between anabolic and catabolic processes in ECM synthesis is disrupted, which ultimately leads to the onset of a degenerative process associated with biomechanical modifications and discogenic lombalgia [9].
Currently, discogenic lombalgia is managed by pharmacological treatments and, if unsuccessful, by invasive surgical procedures (spine fusion or arthroplasty) as a last resort. The clinical success rates following spine fusion is generally reported to be between 50% and 70% [[10], [11], [12]]. An additional morbidity associated with spine fusion is the development of adjacent level degeneration that is often associated with additional surgery [[13], [14], [15], [16]]. Moreover, the cost of spine fusion surgery is substantial and includes additional costs associated with the long recovery time, and possibly from permanent impairments. Regarding arthroplasty (total disc replacement, TDR), a meta-analysis of randomized controlled trials showed a similar safety and efficacy for TDR compared with spine fusion at 2-year follow-up with TDR superior in improving physical function, decreasing pain, and shortening the duration of hospitalization [17]. Nevertheless, an earlier systematic review suggested that the spine surgery community should be prudent in adopting arthroplasty on a large scale because complications may occur after some years [18].
Faced with the limitations of these treatments, and considering the recent knowledge on the mechanisms underlying the pathophysiology of DDD, notably the critical role of resident NP cell depletion in IVD degeneration, regenerative medicine offers new hope for the treatment of DDD [[19], [20], [21]].
Approaches based on NP supplementation (cell therapy) with functional cells, associated or not with biomaterials, were first developed approximately twenty years ago and now offer a potential solution for the prevention of DDD. Various pre-clinical studies have been carried out and have partially confirmed the proof of concept of such a regenerative cellular approach [[22], [23], [24], [25]]. In parallel, the effectiveness of cell therapy in human pilot studies has also been evaluated [26].
Recently, the discovery of cells exhibiting stemness properties and residing in a multitude of tissues/organs has substantiated theories about the presence of populations of reparative cells in developed organisms and has led to a growing interest in the development of endogenous repair strategies [27]. Interestingly, such stem/progenitor cells have been recently discovered in the IVD vicinity and within the NP [[28], [29], [30], [31], [32], [33], [34], [35], [36]]. Nevertheless, their role in regenerative or repair endogenous processes remains poorly understood. It is however tempting to speculate that they could constitute a reservoir of reparative cells potentially able to reverse or slow down DDD [[28], [29], [30], [31], [32], [33], [34], [35], [36]].
A bioinspired strategy could involve the activation of this reservoir of reparative cells, localized in specific anatomical niches, by specific signals such as those arising from injury. Upon activation, these cells would divide and produce daughter cells, which would then differentiate into the required cell type to repair or regenerate the damaged tissue. In this context, the recruitment of endogenous reparative cells might constitute an alternative strategy to exogenous cell transplantation. This bioinspired endogenous repair strategy could provide new therapeutic options for the stimulation and regeneration of the IVD microenvironment. Such strategies would be technically less complex and less costly than approaches that require substantial in vitro cell manipulation and transplantation. Nevertheless, such regenerative strategies would have several difficulties that would need to be overcome, such as the capacity to attract and stimulate reparative cells in situ as well as the maintenance of their efficacy over a long period of time.
This review aims firstly to review the research conducted in the past twenty years using conventional approaches based on exogenous cell transplantation, and will then focus on the new concept of regenerative medicine based on endogenous repair. The review will also discuss the lessons learned about the IVD pathophysiology and document how we can unlock the potential of novel, bioinspired, endogenous approaches.
Section snippets
Cell sources
IVD cell-based therapies for treating DDD, particularly NP supplementation by direct intradiscal injection, have gathered considerable attention over the past two decades. The major cell-based approaches are summarized in Fig. 2 and categorized according to cell type and source (Table 1). All these approaches aim to (i) restore the altered ECM by supplementing the NP with cells already differentiated into NPCy-like cells in vitro or able to undergo such a differentiation in situ once
From exogenous cell transplantation to bioinspired endogenous repair strategies
Although NPCy residing in the adult NP are considered to be the terminal differentiation product of NTC, numerous studies in the literature have highlighted the heterogeneity of the NP cell population [184]. This complexity becomes greater with aging and at early stages of degeneration, raising the idea that progenitor cells other than the NTC may contribute to the heterogeneous nature of NP cells in the adult IVD. These findings have prompted the search for endogenous stem/progenitor cells
Conclusion
IVD cell-based therapies and endogenous repair strategies have the common goal of helping clinicians manage patients suffering from discogenic LBP. It should be stressed that intradiscal injection of exogenous cells has shown attractive results albeit to a lower extent than initially expected. Many obstacles have been identified, particularly the lack of understanding of IVD pathophysiology. The clinical expansion of cell therapy is also limited by regulatory and technological problems as well
References (271)
- et al.
The economic burden of low back pain: a review of studies published between 1996 and 2001
Best Pract. Res. Clin. Rheumatol.
(2002) - et al.
Burden of disability due to musculoskeletal (MSK) disorders
Best Pract. Res. Clin. Rheumatol.
(2014) - et al.
Non-specific low back pain
Lancet
(2017) - et al.
The intervertebral disc: from pathophysiology to tissue engineering
Joint Bone Spine
(2009) - et al.
Lumbar disc arthroplasty
Spine J.
(2005) - et al.
Lumbar instrumented fusion compared with cognitive intervention and exercises in patients with chronic back pain after previous surgery for disc herniation: a prospective randomized controlled study
Pain
(2006) - et al.
Intervertebral disc regeneration: a great challenge for tissue engineers
Trends Biotechnol.
(2014) - et al.
Tissue engineering approaches to degenerative disc disease–a meta-analysis of controlled animal trials
Osteoarthr. Cartil.
(2012) - et al.
Efficacy of intervertebral disc regeneration with stem cells - a systematic review and meta-analysis of animal controlled trials
Gene
(2015) - et al.
The effects of microenvironment in mesenchymal stem cell-based regeneration of intervertebral disc
Spine J.
(2013)
Clinical experience in cell-based therapeutics: disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc
Biomol. Eng.
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
Cell
Live imaging and genetic analysis of mouse notochord formation reveals regional morphogenetic mechanisms
Dev. Cell
Transplanted mesenchymal stem cells with pure fibrinous gelatin-transforming growth factor-beta1 decrease rabbit intervertebral disc degeneration
Spine J.
Construction of tissue-engineered composite intervertebral disc and preliminary morphological and biochemical evaluation
Biochem. Biophys. Res. Commun.
An injectable hydrogel incorporating mesenchymal precursor cells and pentosan polysulphate for intervertebral disc regeneration
Biomaterials
Feasibility of a stem cell therapy for intervertebral disc degeneration
Spine J.
Expenditures and health status among adults with back and neck problems
JAMA
The prevalence of low back pain: a systematic review of the literature from 1966 to 1998
J. Spinal Disord.
Lumbar disc disorders and low-back pain: socioeconomic factors and consequences
J. Bone Joint Surg. Am.
The health and productivity cost burden of the "top 10" physical and mental health conditions affecting six large U.S. employers in 1999
J. Occup. Environ. Med.
Low back pain in relation to lumbar disc degeneration
Spine
Trends and variations in the use of spine surgery
Clin. Orthop. Relat. Res.
Lumbar disc arthroplasty: a critical review
Clin. Neurosurg.
Adjacent segment degeneration in the lumbar spine
J. Bone Joint Surg. Am.
Randomized clinical trial of lumbar instrumented fusion and cognitive intervention and exercises in patients with chronic low back pain and disc degeneration
Spine
Lumbar adjacent segment degeneration and disease after arthrodesis and total disc arthroplasty
Spine
Artificial total disc replacement versus fusion for lumbar degenerative disc disease: a meta-analysis of randomized controlled trials
Arch. Orthop. Trauma Surg.
Total disc replacement surgery for symptomatic degenerative lumbar disc disease: a systematic review of the literature
Eur. Spine J.
Cell-based therapy for disc repair
Spine J.
Future perspectives of cell-based therapy for intervertebral disc disease
Eur. Spine J.
Cell-based therapies used to treat lumbar degenerative disc disease: a systematic review of animal studies and human clinical trials
Stem Cells Int.
Biological treatment approaches for degenerative disk disease: a literature review of in vivo animal and clinical data
Glob. Spine J.
Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study
Transplantation
The stem cell niche should be a key issue for cell therapy in regenerative medicine
Stem Cell Rev. Rep.
Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: a study in four species
Spine
The presence of local mesenchymal progenitor cells in human degenerated intervertebral discs and possibilities to influence these in vitro: a descriptive study in humans
Stem Cells Dev.
Isolation and characterization of mesenchymal stromal cells from human degenerated nucleus pulposus: comparison with bone marrow mesenchymal stromal cells from the same subjects
Spine
Evidence for skeletal progenitor cells in the degenerate human intervertebral disc
Spine
Identification of rabbit annulus fibrosus-derived stem cells
PLoS One
CCL5/RANTES is a key chemoattractant released by degenerative intervertebral discs in organ culture
Eur. Cell. Mater.
Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc
Nat. Commun.
Notochordal cells protect nucleus pulposus cells from degradation and apoptosis: implications for the mechanisms of intervertebral disc degeneration
Arthritis Res. Ther.
Cell transplantation in lumbar spine disc degeneration disease
Eur. Spine J.
Porcine intervertebral disc repair using allogeneic juvenile articular chondrocytes or mesenchymal stem cells
Tissue Eng. A
Multilineage potential of adult human mesenchymal stem cells
Science
Role of hypoxia and growth and differentiation factor-5 on differentiation of human mesenchymal stem cells towards intervertebral nucleus pulposus-like cells
Eur. Cell. Mater.
Growth differentiation factor 6 and transforming growth factor-beta differentially mediate mesenchymal stem cell differentiation, composition, and micromechanical properties of nucleus pulposus constructs
Arthritis Res. Ther.
TGF-b1 and GDF5 act synergistically to drive the differentiation of human adipose stromal cells toward nucleus pulposus-like cells
Stem Cells
Induced pluripotent stem cell-derived mesenchymal stem cells: progress toward safe clinical products
Stem Cells
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Acknowledgements: This review was supported by grants from Société Française de Neurochirurgie, Société Française de Chirurgie du Rachis, Agence de la Biomédecine, Institut National de la Santé et de la Recherche Médicale (INSERM), Région des Pays de la Loire (“Paris scientifiques” BIO2, “Poste stratégique” DIVA, “Nouvelle équipe” BIODIV and “RFI Bioregate” Caveodisc project), ANR génériques 2014 (REMEDIV project), ANR JCJC 2016 (STIMUDISC project), Fondation pour la Recherche Médicale FRM Bioingénierie (DBS20131128442, REMEDIV project), Fondation de l'Avenir pour la Recherche Médicale Appliquée (BO-RMA-15-001), Société Arthritis R&D (Notoch project) and the Research Program Longévité Mobilité Autonomie (LMA). The authors gratefully acknowledge Sophie Domingues for editing the manuscript.
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