Differentiation of MSC and annulus fibrosus cells on genetically engineered silk fleece‐membrane‐composites enriched for GDF‐6 or TGF‐β3

Frauchiger, Daniela Angelika; Heeb, Silvan; May, Rahel Deborah; Wöltje, Michael; Benneker, Lorin Michael; Gantenbein, Benjamin

doi:10.1002/jor.23778

Cited by 25 publications

(27 citation statements)

References 45 publications

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“…However, it is worth noting that a study assessing the response of human mesenchymal stem cells (MSCs) and AF cells to silk constructs with and without GDF6 added exogenously, or presented within the silk construct, stimulated matrix gene expression in MSCs but not AF cells. Therefore, it may be necessary to treat the AF region of the degenerate IVDs with an additional growth factor, delivering GDF6 to the NP region only [ 36 ]. Further work is required to identify the best solution for AF regeneration.…”

Section: Discussionmentioning

confidence: 99%

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation

Hodgkinson

Gilbert

Pandya

et al. 2020

IJMS

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Growth differentiation factor (GDF) family members have been implicated in the development and maintenance of healthy nucleus pulposus (NP) tissue, making them promising therapeutic candidates for treatment of intervertebral disc (IVD) degeneration and associated back pain. GDF6 has been shown to promote discogenic differentiation of mesenchymal stem cells, but its effect on NP cells remains largely unknown. Our aim was to investigate GDF6 signalling in adult human NP cells derived from degenerate tissue and determine the signal transduction pathways critical for GDF6-mediated phenotypic changes and tissue homeostatic mechanisms. This study demonstrates maintained expression of GDF6 receptors in human NP and annulus fibrosus (AF) cells across a range of degeneration grades at gene and protein level. We observed an anabolic response in NP cells treated with recombinant GDF6 (increased expression of matrix and NP-phenotypic markers; increased glycosaminoglycan production; no change in catabolic enzyme expression), and identified the signalling pathways involved in these responses (SMAD1/5/8 and ERK1/2 phosphorylation, validated by blocking studies). These findings suggest that GDF6 promotes a healthy disc tissue phenotype in degenerate NP cells through SMAD-dependent and -independent (ERK1/2) mechanisms, which is important for development of GDF6 therapeutic strategies for treatment of degenerate discs.

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Section: Discussionmentioning

confidence: 99%

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation

Hodgkinson

Gilbert

Pandya

et al. 2020

IJMS

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“…Furthermore, also here, no adverse effects due to the genipin were observed. Additionally, the silk composite might be used to culture or condition cells prior AF repair, when engineered to contain growth factors such as GDF-6 [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

“…Silk is an uttermost exciting biomaterial and has been proposed in orthopaedics for many applications including bone-, anterior cruciate ligament-, tendon-, meniscus-, and IVD repair [ 8 , 9 , 10 , 11 ]. Silk keeps in the research focus since it is resorbable, fine-tuneable for slow release of incorporated growth factors [ 12 ] and can be liquefied or applied in different knitted forms or also in modern concepts of [ 8 , 13 , 14 , 15 ]. Silk has outstanding tensile strengths and low inflammatory response characteristics if applied degummed from sericin [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…The repaired IVDs were then compared to the injury only group and normalized to healthy control IVDs. The three experimental groups were subjected to either no loading, static loading or complex loading conditions [ 12 ]. To mimic physiological loads, complex loading was performed in a two-degree-of-freedom bioreactor that allows for compression and torsion [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Genipin-Enhanced Fibrin Hydrogel and Novel Silk for Intervertebral Disc Repair in a Loaded Bovine Organ Culture Model

Frauchiger

May

Bakırcı

et al. 2018

JFB

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(1) Background: Intervertebral disc (IVD) repair represents a major challenge. Using functionalised biomaterials such as silk combined with enforced hydrogels might be a promising approach for disc repair. We aimed to test an IVD repair approach by combining a genipin-enhanced fibrin hydrogel with an engineered silk scaffold under complex load, after inducing an injury in a bovine whole organ IVD culture; (2) Methods: Bovine coccygeal IVDs were isolated from ~1-year-old animals within four hours post-mortem. Then, an injury in the annulus fibrosus was induced by a 2 mm biopsy punch. The repair approach consisted of genipin-enhanced fibrin hydrogel that was used to fill up the cavity. To seal the injury, a Good Manufacturing Practise (GMP)-compliant engineered silk fleece-membrane composite was applied and secured by the cross-linked hydrogel. Then, IVDs were exposed to one of three loading conditions: no load, static load and complex load in a two-degree-of-freedom bioreactor for 14 days. Followed by assessing DNA and matrix content, qPCR and histology, the injured discs were compared to an uninjured control IVD that underwent the same loading profiles. In addition, the genipin-enhanced fibrin hydrogel was further investigated with respect to cytotoxicity on human stem cells, annulus fibrosus, and nucleus pulposus cells; (3) Results: The repair was successful as no herniation could be detected for any of the three loading conditions. Disc height was not recovered by the repair DNA and matrix contents were comparable to a healthy, untreated control disc. Genipin resulted being cytotoxic in the in vitro test but did not show adverse effects when used for the organ culture model; (4) Conclusions: The current study indicated that the combination of the two biomaterials, i.e., genipin-enhanced fibrin hydrogel and an engineered silk scaffold, was a promising approach for IVD repair. Furthermore, genipin-enhanced fibrin hydrogel was not suitable for cell cultures; however, it was highly applicable as a filler material.

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“…For this reason, preexposing MSCs in vitro to such growth factors before implantation or embed-ding them in MSC-loaded bioscaffolds could maintain their biological activity and boost cell proliferation, differentiation, and synthetic potential [37]. Several in vitro and preclinical studies have been conducted in this regard [79][80][81][82][83].…”

Section: Stem Cells Internationalmentioning

confidence: 99%

Interaction between Mesenchymal Stem Cells and Intervertebral Disc Microenvironment: From Cell Therapy to Tissue Engineering

Vadalà

Ambrosio

Russo

et al. 2019

Stem Cells International

112

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Low back pain (LBP) in one of the most disabling symptoms affecting nearly 80% of the population worldwide. Its primary cause seems to be intervertebral disc degeneration (IDD): a chronic and progressive process characterized by loss of viable cells and extracellular matrix (ECM) breakdown within the intervertebral disc (IVD) especially in its inner region, the nucleus pulposus (NP). Over the last decades, innovative biological treatments have been investigated in order to restore the original healthy IVD environment and achieve disc regeneration. Mesenchymal stem cells (MSCs) have been widely exploited in regenerative medicine for their capacity to be easily harvested and be able to differentiate along the osteogenic, chondrogenic, and adipogenic lineages and to secrete a wide range of trophic factors that promote tissue homeostasis along with immunomodulation and anti-inflammation. Several in vitro and preclinical studies have demonstrated that MSCs are able to acquire a NP cell-like phenotype and to synthesize structural components of the ECM as well as trophic and anti-inflammatory mediators that may support resident cell activity. However, due to its unique anatomical location and function, the IVD presents distinctive features: avascularity, hypoxia, low glucose concentration, low pH, hyperosmolarity, and mechanical loading. Such conditions establish a hostile microenvironment for both resident and exogenously administered cells, which limited the efficacy of intradiscal cell therapy in diverse investigations. This review is aimed at describing the characteristics of the healthy and degenerated IVD microenvironment and how such features influence both resident cells and MSC viability and biological activity. Furthermore, we focused on how recent research has tried to overcome the obstacles coming from the IVD microenvironment by developing innovative cell therapies and functionalized bioscaffolds.

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Differentiation of MSC and annulus fibrosus cells on genetically engineered silk fleece‐membrane‐composites enriched for GDF‐6 or TGF‐β3

Cited by 25 publications

References 45 publications

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation

Genipin-Enhanced Fibrin Hydrogel and Novel Silk for Intervertebral Disc Repair in a Loaded Bovine Organ Culture Model

Interaction between Mesenchymal Stem Cells and Intervertebral Disc Microenvironment: From Cell Therapy to Tissue Engineering

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