Potential regenerative treatment strategies for intervertebral disc degeneration in dogs

Bach, Frances C.; Willems, Nicole; Penning, Louis C.; Ito, Keita; Meij, Björn P.; Tryfonidou, Marianna A.

doi:10.1186/1746-6148-10-3

Cited by 48 publications

(43 citation statements)

References 94 publications

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“…Cell expansion for one or more passages likely induced dedifferentiation of the CLCs, a wellknown phenomenon for articular chondrocytes (Bekkers et al, 2014;Veilleux et al, 2004). Since dedifferentiated CLCs could respond differently from freshly isolated CLCs (P0), future studies should determine the effect of (species-specific) NCCM on P0 CLCs and explants.…”

Section: Limitations Of the Studymentioning

confidence: 99%

“…anti-inflammatory, anti-neurogenic and antiangiogenic effects by secreting factors as sonic hedgehog, noggin, connective tissue growth factor and chondroitin sulphate (Cornejo et al, 2015;Gantenbein et al, 2014;Purmessur et al, 2013a). Thus, NCs secrete factors with auspicious potential, making them an interesting target for regenerative and/or symptom modifying therapies (Bach et al, 2014). NC-based regenerative strategies are being developed, using canine non-chondrodystrophic (NCD) and porcine donors because of easy availability of their NC-rich NP tissue (Bach et al, 2014).…”

Section: Ncs Of Different Species Regenerate Human Clcsmentioning

confidence: 99%

“…Thus, NCs secrete factors with auspicious potential, making them an interesting target for regenerative and/or symptom modifying therapies (Bach et al, 2014). NC-based regenerative strategies are being developed, using canine non-chondrodystrophic (NCD) and porcine donors because of easy availability of their NC-rich NP tissue (Bach et al, 2014). Although regenerative effects of canine and porcine NC-secreted factors on human CLCs/MSCs have been demonstrated in several studies (Abbott et al, 2012;Korecki et al, 2010;Mehrkens et al, 2013;Purmessur et al, 2011), the impact of human NC-secreted factors has never been determined, most probably due to limited availability of human NC-rich NP tissue.…”

Section: Ncs Of Different Species Regenerate Human Clcsmentioning

confidence: 99%

“…Primer uniqueness and specificity was determined using BLAST (Altschul et al, 1997). Annealing temperatures were established by performing a temperature gradient PCR on a 16-fold dilution series.…”

Section: Gene Expression Of the Human Clc Micro-aggregatesmentioning

confidence: 99%

“…For this reason, regenerative strategies like gene-, growth factor-or cellbased therapies, that try to repair the degenerated IVD biologically, have gained increasing interest (Bach et al, 2014;Gilbert et al, 2013). They either aim at increasing the cell numbers by cell transplantation and/or by stimulating proliferation of the resident cells or matrix anabolism.…”

Section: Introductionmentioning

confidence: 99%

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The species-specific regenerative effects of notochordal cell-conditioned medium on chondrocyte-like cells derived from degenerated human intervertebral discs

Bach

Vries

Krouwels

et al. 2015

eCM

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During intervertebral disc (IVD) maturation, the main cell type shifts from notochordal cells (NCs) to chondrocytelike cells (CLCs). NCs secrete factors with regenerative potential, making them an interesting focus for regenerative treatments. During initial development, these strategies preferably employ non-human donors due to easy availability of their NC-rich nucleus pulposus (NP) tissue. To increase the success of translating these strategies for clinical application, this study aimed to delineate whether NC-secreted factors of different species have a regenerative effect on human CLCs. Human, canine and porcine NC-rich NP tissue and NC-conditioned medium (NCCM) were analysed biochemically and histologically. Human CLC micro-aggregates from degenerated IVDs were cultured in human, canine or porcine NCCM. Collagen, glycosaminoglycan (GAG) and DNA content was determined and histology was performed. Canine and porcine NPs were richer in NCs than human NPs. Human NPs contained the highest collagen content, whereas the DNA and GAG content of canine NPs was significantly higher than that of human or porcine NPs. NCCM from all species significantly increased the DNA and GAG content of the human CLC micro-aggregates. Porcine and canine NCCM were significantly more potent than human NCCM in inducing GAG deposition, whereas only human NCCM induced collagen type II production. Secreted factors from human, canine and porcine NC-rich NPs exerted regenerative effects on human CLCs, indicating a cross-species effect. Bioactive compound(s) are present in NCCM of different species that may reverse human IVD degeneration, supporting further research into strategies based on NC-technology employing canine or porcine models for their translation into humans.

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Section: Limitations Of the Studymentioning

confidence: 99%

Section: Ncs Of Different Species Regenerate Human Clcsmentioning

confidence: 99%

Section: Ncs Of Different Species Regenerate Human Clcsmentioning

confidence: 99%

Section: Gene Expression Of the Human Clc Micro-aggregatesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The species-specific regenerative effects of notochordal cell-conditioned medium on chondrocyte-like cells derived from degenerated human intervertebral discs

Bach

Vries

Krouwels

et al. 2015

eCM

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Leptin accelerates BMSC transformation into vertebral epiphyseal plate chondrocytes by activating SENP1‐mediated deSUMOylation of SIRT3

et al. 2023

FEBS Open Bio

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Bone marrow mesenchymal stem cells (BMSCs) are capable of multidirectional differentiation, and engrafted BMSCs can be used to replace damaged chondrocytes for treatment of intervertebral disc disease. However, chondroblast differentiation of implanted BMSCs is inhibited by the anoxic environment of the articular cavity. Here, we found that leptin enhanced the transformation of BMSCs into chondrocytes under hypoxic conditions. BMSCs isolated from mice were cultured in medium supplemented with leptin under hypoxia. The expression of MFN1/2 and OPA1 were increased only in BMSCs cultured in an anoxic environment. In addition, in hypoxic environments cell energy metabolism relies on glycolysis regulated by leptin, rather than by mitochondrial oxidation. The expression of the de‐SUMOylation protease SENP1 was elevated, leading to SIRT3‐mediated activation of PGC‐1α; these processes were regulated by CREB phosphorylation, and promoted mitochondrial fusion and cell differentiation. The chondrogenic activity of BMSCs isolated from SIRT3‐knockout mice was lower than that of BMSCs isolated from wildtype mice. Implantation of SIRT3‐knockout murine‐derived BMSCs did not significantly improve the articular cartilage layer of the disc. In conclusion, the hypoxic microenvironment promoted BMSC differentiation into chondrocytes, whereas osteoblast differentiation was inhibited. SENP1 activated SIRT3 through the deSUMOylation of mitochondria and eliminated the antagonistic effect of SIRT3 acetylation on phosphorylation. When phosphorylation activity of CREB was increased, phosphorylated CREB is then transferred to the nucleus, affecting PGC‐1α. This promotes mitochondrial fusion and differentiation of BMSCs. Leptin not only maintains chondrogenic differentiation homeostasis of BMSCs, but also provides energy for differentiation of BMSCs under hypoxic conditions through glycolysis.

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Inorganic polyphosphates enhances nucleus pulposus tissue formation in vitro

Gawri

Shiba

Pilliar

et al. 2016

Journal Orthopaedic Research

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Disc degeneration is associated with low back pain for which currently there is no optimal therapy so there is a great need to identify new treatment approaches. Inorganic polyphosphates (polyP) are linear polymers of orthophosphate units varying in chain length and present in many cell types. As polyP has anabolic effects on chondrocytes, we hypothesized that polyP treatment would enhance matrix accumulation by nucleus pulposus (NP) cells. NP cells isolated from bovine caudal discs were grown in 3D culture under normoxic or in select experiments under hypoxic conditions, in the presence or absence of various concentrations and sizes of polyP. Gene expression was determined using RT-PCR. Matrix accumulation was quantified by measuring proteoglycan and collagen contents. DAPI fluorescence shift was used to stain for polyP in tissue. DAPI staining showed polyP present predominantly in the pericellular region of in vitro formed tissue. PolyP treatment enhanced matrix accumulation in a concentration and chain length dependant manner. NP cells exposed to polyP-22 (22 phosphate units length) showed an increase in gene expression of aggrecan, Collagen II, Sox 9, and MMP-13 which was maintained for the 14 days of culture. This suggests that polyP may enhance NP tissue formation in vitro by upregulating the expression of matrix genes. As polyP enhances proteoglycan accumulation even under hypoxic conditions, this raises the possibility that polyP may be a novel treatment to induce NP regeneration. ß

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Potential regenerative treatment strategies for intervertebral disc degeneration in dogs

Cited by 48 publications

References 94 publications

The species-specific regenerative effects of notochordal cell-conditioned medium on chondrocyte-like cells derived from degenerated human intervertebral discs

The species-specific regenerative effects of notochordal cell-conditioned medium on chondrocyte-like cells derived from degenerated human intervertebral discs

Leptin accelerates BMSC transformation into vertebral epiphyseal plate chondrocytes by activating SENP1‐mediated deSUMOylation of SIRT3

Inorganic polyphosphates enhances nucleus pulposus tissue formation in vitro

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