2019
DOI: 10.1016/j.joca.2018.09.001
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CRISPR-Cas9 targeting of MMP13 in human chondrocytes leads to significantly reduced levels of the metalloproteinase and enhanced type II collagen accumulation

Abstract: CRISPR-Cas9 mediated genome editing can be used to efficiently and reproducibly establish populations of human chondrocytes with stably reduced expression of key genes of interest without the need for clonal selection. Such an editing approach has the potential to greatly enhance current cell-based therapies for cartilage repair.

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Cited by 40 publications
(19 citation statements)
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“…To this aim, we isolated enriched mesenchymal stromal/stem population from 6-months SAMP8 and SAMR1 mice after bone marrow flushing, and 2 weeks of selection for cell culture adhesion as previously published [32]. Several cell cycle inhibitors associated with senescence state such as p16 INK4a , p19 ARF and p21 Cdkn1a , and some SASP factors namely TGF-β1 and MMP-13, were upregulated in SAMP8 MSCs compared with SAMR1 MSCs (Figure 5A) [18, 33, 34]. As expected for senescent cells, these SAMP8 MSCs showed also an increase in SA-β-galactosidase activity (Figure 5B) but a surprisingly non-classical inflammatory SASP as demonstrated by absence in IL-6 and IL-1β expression levels (Figure 5A).…”
Section: Resultsmentioning
confidence: 99%
“…To this aim, we isolated enriched mesenchymal stromal/stem population from 6-months SAMP8 and SAMR1 mice after bone marrow flushing, and 2 weeks of selection for cell culture adhesion as previously published [32]. Several cell cycle inhibitors associated with senescence state such as p16 INK4a , p19 ARF and p21 Cdkn1a , and some SASP factors namely TGF-β1 and MMP-13, were upregulated in SAMP8 MSCs compared with SAMR1 MSCs (Figure 5A) [18, 33, 34]. As expected for senescent cells, these SAMP8 MSCs showed also an increase in SA-β-galactosidase activity (Figure 5B) but a surprisingly non-classical inflammatory SASP as demonstrated by absence in IL-6 and IL-1β expression levels (Figure 5A).…”
Section: Resultsmentioning
confidence: 99%
“…Briefly, this system is encoded with a specific RNA to guide the enzyme Cas9 to a desired target for cleavage. Through the targeted down regulation of matrix metalloprotein-13 (MMP13), generated chondrocytes can increase expression of collagen II [110]. This means gene editing of targets could convey chondrogenic advantages to cells and increase the potential of superior articular cartilage repair.…”
Section: Discussionmentioning
confidence: 99%
“…27 Seidl et al targeted a bulk population of primary human chondrocytes with the RNP version of CRISPR/Cas9 to initiate a reduction in functional MMP-13. 28 While single-cell derived colonies were not selected in this study, generating NHEJ in the coding region of MMP-13 was sufficient to reduce the level of MMP-13 in the bulk cell population. Because MMP-13 is a secreted factor that compromises function at the tissue level, the reduced MMP-13 resulted in a higher quality engineered tissue.…”
Section: Discussionmentioning
confidence: 99%