The potential of CRISPR/Cas9 genome editing for the study and treatment of intervertebral disc pathologies

Krupková, Olga; Cambria, Elena; Besse, Lenka; Besse, Andrej; Bowles, Robert D.; Wuertz‐Kozak, Karin

doi:10.1002/jsp2.1003

Cited by 28 publications

(28 citation statements)

References 122 publications

(201 reference statements)

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“…Further studies including modulation of TRPC6 (with, e.g. activation with CRISPRa or knockout with CRISPRi [37]) are needed to reveal the possible involvement of TRPC6 in IVD mechanotransduction.…”

Section: Discussionmentioning

confidence: 99%

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TRPC6 in simulated microgravity of intervertebral disc cells

et al. 2018

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Purpose Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs. Methods Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5 days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed. Results Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3 days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity. Conclusions Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies.Graphical abstract These slides can be retrieved under Electronic Supplementary Material.

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Section: Discussionmentioning

confidence: 99%

“…So far, TRPC6 modulation has been investigated for focal segmental glomerulosclerosis [50], pulmonary hypertension [51] and ischaemia reperfusion-induced lung oedema [52]. TRP channel modulation could be achieved by gene editing, using CRIPSR/ Cas9 [37,53,54]. However, these approaches are still in an early experimental phase.…”

Section: Discussionmentioning

confidence: 99%

TRPC6 in simulated microgravity of intervertebral disc cells

et al. 2018

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“…While current treatment options for DDD, including oral analgesics and surgery, solely aim to reduce the symptoms, researchers have made extensive efforts over the past decade to develop novel therapeutic approaches that target the underlying pathophysiological mechanisms, i.e., degeneration, inflammation, and enhanced apoptosis (Fernandez-Moure et al, 2018;Tendulkar et al, 2019). A wide range of approaches has been tested which are described in detail elsewhere (Krupkova et al, 2018;Smith et al, 2018;Clouet et al, 2019;Hodgkinson et al, 2019;Loibl et al, 2019), ranging from autologous disc cell therapy, growth factors, biologics, gene transfection, and biomaterials to CRISPR/Cas9 genome engineering, as well as the use of mesenchymal stem cells (MSCs). However, none of these concepts have been successfully incorporated yet into daily clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Extracellular Vesicles in Degenerative Diseases of the Intervertebral Disc

Piazza

Dehghani

Gaborski

et al. 2020

Front. Bioeng. Biotechnol.

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Extracellular vesicles (EVs) are lipid membrane particles carrying proteins, lipids, DNA, and various types of RNA that are involved in intercellular communication. EVs derived from mesenchymal stem cells (MSCs) have been investigated extensively in many different fields due to their crucial role as regeneration drivers, but research for their use in degenerative diseases of the intervertebral disc (IVD) has only started recently. MSC-derived EVs not only promote extracellular matrix synthesis and proliferation in IVD cells, but also reduce apoptosis and inflammation, hence having multifunctional beneficial effects that seem to be mediated by specific miRNAs (such as miR-233 and miR-21) within the EVs. Aside from MSC-derived EVs, IVD-derived EVs (e.g., stemming from notochordal cells) also have important functions in IVD health and disease. This article will summarize the current knowledge on MSC-derived and IVDderived EVs and will highlight areas of future research, including the isolation and analysis of EV subpopulations or exposure of MSCs to cues that may enhance the therapeutic potential of released EVs.

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“…CRISPR/Cas9 could for example be used to protect MSCs from the inflammatory IVD microenvironment by repressing the expression of cytokine receptors . Other possible applications of MSC‐targeted genome editing with excellent potential for IVD regeneration may entail inhibition of cell senescence (eg, by inhibition of p16 by CRISPRi) as well as activation of extracellular matrix protein expression (eg, induced synthesis of aggrecan by CRISPRa) …”

Section: Yesmentioning

confidence: 99%

Controversies in regenerative medicine: Should intervertebral disc degeneration be treated with mesenchymal stem cells?

Loibl¹,

et al. 2019

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Low back pain (LBP) can significantly reduce the quality of life of patients, and has a considerable economic and social impact worldwide. It is commonly associated with disc degeneration, even though many people with degenerate discs are asymptomatic. Degenerate disc disease (DDD), is thus a common term for intervertebral disc (IVD) degeneration associated with LBP. Degeneration is thought to lead to LBP because of nerve ingrowth into the degenerate disc, inflammation, or because degradation of extracellular matrix (ECM) alters spinal biomechanics inappropriately. Thus, while the objectives of some interventions for LBP are to control pain intensity, other interventions aim to deal with the consequences of disc degeneration through stabilizing the disc surgically, by inserting artificial discs or by repairing the disc biologically and preventing progressive IVD degeneration. Despite tremendous research efforts, treatment of LBP through the use of regenerative interventions aiming to repair the IVD is still controversial. The use of mesenchymal stem cells for IVD regeneration in a patient‐based case will be discussed by an ensemble of clinicians and researchers.

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The potential of CRISPR/Cas9 genome editing for the study and treatment of intervertebral disc pathologies

Cited by 28 publications

References 122 publications

TRPC6 in simulated microgravity of intervertebral disc cells

TRPC6 in simulated microgravity of intervertebral disc cells

Therapeutic Potential of Extracellular Vesicles in Degenerative Diseases of the Intervertebral Disc

Controversies in regenerative medicine: Should intervertebral disc degeneration be treated with mesenchymal stem cells?

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