KLF15 regulates in vitro chondrogenic differentiation of human mesenchymal stem cells by targeting SOX9

Song, Zihui; Lian, Xiaolei; Wang, Yan; Xiang, Ye; Li, Guangheng

doi:10.1016/j.bbrc.2017.09.078

Cited by 17 publications

(9 citation statements)

References 18 publications

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“…KLF15 is a well-characterized transcription factor, and previous studies have demonstrated that KLF15 regulates cell differentiation 19 , 20 , circadian rhythm 21 , 22 , and cellular metabolism 23 . Klf15 deficiency occurs in human cardiomyopathy and aortic aneurysms, and its deletion leads to cardiomyopathy and aortopathy in mice 24 .…”

Section: Discussionmentioning

confidence: 99%

A defect in mitochondrial protein translation influences mitonuclear communication in the heart

Gao

Liang

et al. 2023

Nat Commun

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The regulation of the informational flow from the mitochondria to the nucleus (mitonuclear communication) is not fully characterized in the heart. We have determined that mitochondrial ribosomal protein S5 (MRPS5/uS5m) can regulate cardiac function and key pathways to coordinate this process during cardiac stress. We demonstrate that loss of Mrps5 in the developing heart leads to cardiac defects and embryonic lethality while postnatal loss induces cardiac hypertrophy and heart failure. The structure and function of mitochondria is disrupted in Mrps5 mutant cardiomyocytes, impairing mitochondrial protein translation and OXPHOS. We identify Klf15 as a Mrps5 downstream target and demonstrate that exogenous Klf15 is able to rescue the overt defects and re-balance the cardiac metabolome. We further show that Mrps5 represses Klf15 expression through c-myc, together with the metabolite L-phenylalanine. This critical role for Mrps5 in cardiac metabolism and mitonuclear communication highlights its potential as a target for heart failure therapies.

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Section: Discussionmentioning

confidence: 99%

A defect in mitochondrial protein translation influences mitonuclear communication in the heart

Gao

Liang

et al. 2023

Nat Commun

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“…In particular, Krüppel-like transcription factor 15 (KLF15), has been suggested as a novel factor involved in regulation of chondrogenesis and OA development (Li et al, 2018). KLF15 was demonstrated to play an important role in chondrogenic differentiation in a time-dependent manner by activating the expression of SOX9 via direct binding and promoter initiation (Song et al, 2017). It also has been shown to directly suppress expression of the Matrix metalloproteinase-3 (MMP3) gene.…”

Section: Rspo2 Is a Target Of Mir-181amentioning

confidence: 99%

MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells

Melnik

Hofmann

Gabler

et al. 2021

Front. Cell Dev. Biol.

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Mechanisms of WNT and bone morphogenetic protein (BMP) signaling crosstalk is in the focus of multiple biological studies, and it also has been discovered to play important roles in human mesenchymal stromal cells (MSC) that are of great interest for neocartilage engineering due to their high chondrogenic differentiation potential. However, MSC-derived chondrocytes undergo hypertrophic degeneration that impedes their clinical application for cartilage regeneration. In our previous study, we established that several microRNAs (miRs) are differentially expressed between articular chondrocytes (AC) – and MSC-derived neocartilage, with miR-181a being the most prominent candidate as key microRNA involved in the regulation of a balance between chondral and endochondral differentiation. The aim of this study was the identification of precise mRNA targets and signaling pathways regulated by miR-181a in MSC during chondrogenesis. MiR-181a was upregulated during chondrogenesis of MSC, along with an increase of the hypertrophic phenotype in resulting cartilaginous tissue. By in silico analysis combined with miR reporter assay, the WNT signaling activator and BMP signaling repressor RSPO2 was suggested as a target of miR-181a. Further validation experiments confirmed that miR-181a targets RSPO2 mRNA in MSC. It was found that in human MSC miR-181a activated BMP signaling manifested by the accumulation of SOX9 protein and increased phosphorylation of SMAD1/5/9. These effects, together with the concomitant reduction of canonical WNT signaling induced by miR-181a mimic, were in accordance with the effects expected by the loss of RSPO2, thus indicating the causative link between miR-181a and RSPO2. Moreover, we observed that a tight correlation between miR-181a and miR-218 expression levels in healthy human cartilage tissue was disrupted in osteoarthritis (OA) highlighting the importance of the WNT-BMP signaling crosstalk for preventing OA.

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“…Pathway analysis suggests that the TGF-β/Smad signaling pathway leads to an activation of SOX9 expression via the osteoarthritis pathway. Also, the TF KLF15 was shown to increase the chondrogenic differentiation potential of bone marrow MSCs by binding to the SOX9 promoter (Song et al 2017). In our study, we find KLF15 co-regulated with SOX9, with both peaking at 2 hours after IOD.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of early differentiation of primary human mesenchymal stem cells into chondrocytes

Schwarzl

Keogh

Shaw

et al. 2021

Preprint

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Articular cartilage has only very limited regenerative capacities in humans. Tissue engineering techniques for cartilage damage repair are limited in the production of hyaline cartilage. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells and can be differentiated into mature cartilage cells, chondrocytes, which could be used for repairing damaged cartilage. Chondrogenesis is a highly complex, relatively inefficient process lasting over 3 weeks in vitro. In order to better understand chondrogenic differentiation, especially the commitment phase, we have performed transcriptional profiling of MSC differentiation into chondrocytes from early timepoints starting 15 minutes after induction to 16 hours and fully differentiated chondrocytes at 21 days. Transcriptional gene regulatory networks (GRN) were identified using time-course clustering and upstream-regulator predictions which revealed that cells start epigenetic reprogramming as early as 2 hours after induction and commit to differentiation within 4-6 hours. After that they adapt their gene expression to cater for differentiation specific protein production. These results suggest that interventions to improve the frequency and efficiency of differentiation should target early processes.

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KLF15 regulates in vitro chondrogenic differentiation of human mesenchymal stem cells by targeting SOX9

Cited by 17 publications

References 18 publications

A defect in mitochondrial protein translation influences mitonuclear communication in the heart

A defect in mitochondrial protein translation influences mitonuclear communication in the heart

MiR-181a Targets RSPO2 and Regulates Bone Morphogenetic Protein – WNT Signaling Crosstalk During Chondrogenic Differentiation of Mesenchymal Stromal Cells

Transcriptional profiling of early differentiation of primary human mesenchymal stem cells into chondrocytes

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