Mtu1 defects are correlated with reduced osteogenic differentiation

He, Qiufen; Zhao, Qiong; Li, Qianqian; Pan, Ruolang; Li, Xiongfeng; Chen, Ye

doi:10.1038/s41419-020-03345-5

Cited by 7 publications

(6 citation statements)

References 46 publications

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“…Active mitochondria promote osteogenic differentiation and their mass increases during osteogenic differentiation. 17 - 20 For this reason, our observation that the increase in mitochondrial stability following GuaRD treatment promotes osteogenic differentiation is important.…”

Section: Resultsmentioning

confidence: 99%

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Strategies for accelerating osteogenesis through nanoparticle-based DNA/mitochondrial damage repair

Kim¹,

Cho²,

Lyu³

et al. 2022

Theranostics

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The efficiency of gene therapy is often dictated by the gene delivery system. Cationic polymers are essential elements of gene delivery systems. The relatively cheap cationic polymer, polyethyleneimine, has high gene delivery efficiency and is often used for gene delivery. However, the efficiency of gene therapy with polyethyleneimine-pDNA polyplex (PEI) is low. Human mesenchymal stem cells transfected with polyethyleneimine and a plasmid carrying the important osteogenic differentiation gene runt-related transcription factor 2 (RUNX2) accumulated DNA double-strand breaks and mitochondrial damage proportional to the amount of polyethyleneimine, reducing viability. Genomic/cellular stabilizer mediating RUNX2 delivery (GuaRD), a new reagent incorporating RS-1 NPs developed in this study, promoted DNA repair and prevented the accumulation of cell damage, allowing the delivery of pRUNX2 into hMSCs. while maintaining genome and mitochondrial stability. DNA damage was significantly lower and the expression of DNA repair-related genes significantly higher with GuaRD than with PEI. In addition, GuaRD improved mitochondrial stability, decreased the level of reactive oxygen species, and increased mitochondrial membrane potential. Osteogenic extracellular matrix (ECM) expression and calcification were higher with GuaRD than with PEI, suggesting improved osteogenic differentiation. These results indicate that lowering the cytotoxicity of PEI and improving cell stability are key to overcoming the limitations of conventional gene therapy, and that GuaRD can help resolve these limitations.

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Section: Resultsmentioning

confidence: 99%

“…Mitochondrial damage slows the differentiation of stem cells. Studies have shown that mitochondrial dysfunction decreases osteogenic differentiation 17 - 19 . In addition, mitochondrial DNA mass increases during osteogenic differentiation 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

Strategies for accelerating osteogenesis through nanoparticle-based DNA/mitochondrial damage repair

Kim¹,

Cho²,

Lyu³

et al. 2022

Theranostics

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“…MSCs were isolated and purified through their physical adherence to the plastic cell culture plate as previously described. [ 4a,33 ] Cells were harvested before reaching confluence by applying 0.25% trypsin and 1 × 10 −3 m EDTA (Invitrogen). Then, MSCs were checked for positivity of CD105, CD73, and CD90 and the lack of expression of CD45 and CD34 using flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities

et al. 2022

Self Cite

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Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient-derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation-dependent manner. Mechanistic studies identify that AML cell-derived exosomes play a vital role during the AML cell-mediated MSCs education/reprogramming process. Pre-administration of mice BM microenvironment with AML-derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML-derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome-based AML cells-MSCs communication. Collectively, the data show that AML-educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.

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“…Following harvest, 4 weeks of samples ( n = 5 for each group) were sent for microcomputed tomography (μCT) evaluation. Each tibia was scanned using a U-CT system (MILabsU-CT, Netherlands), and the operation parameters were based on a previous report [ 53 ].…”

Section: Methodsmentioning

confidence: 99%

Knockdown of FOXA1 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells partly via activation of the ERK1/2 signalling pathway

Wang

et al. 2022

Stem Cell Res Ther

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Background The available therapeutic options for large bone defects remain extremely limited, requiring new strategies to accelerate bone healing. Genetically modified bone mesenchymal stem cells (BMSCs) with enhanced osteogenic capacity are recognised as one of the most promising treatments for bone defects. Methods We performed differential expression analysis of miRNAs between human BMSCs (hBMSCs) and human dental pulp stem cells (hDPSCs) to identify osteogenic differentiation-related microRNAs (miRNAs). Furthermore, we identified shared osteogenic differentiation-related miRNAs and constructed an miRNA-transcription network. The Forkhead box protein A1 (FOXA1) knockdown strategy with a lentiviral vector was used to explore the role of FOXA1 in the osteogenic differentiation of MSCs. Cell Counting Kit-8 was used to determine the effect of the knockdown of FOXA1 on hBMSC proliferation; real-time quantitative reverse transcription PCR (qRT-PCR) and western blotting were used to investigate target genes and proteins; and alkaline phosphatase (ALP) staining and Alizarin Red staining (ARS) were used to assess ALP activity and mineral deposition, respectively. Finally, a mouse model of femoral defects was established in vivo, and histological evaluation and radiographic analysis were performed to verify the therapeutic effects of FOXA1 knockdown on bone healing. Results We identified 22 shared and differentially expressed miRNAs between hDPSC and hBMSC, 19 of which were downregulated in osteogenically induced samples. The miRNA-transcription factor interaction network showed that FOXA1 is the most significant and novel osteogenic differentiation biomarker among more than 300 transcription factors that is directly targeted by 12 miRNAs. FOXA1 knockdown significantly promoted hBMSC osteo-specific genes and increased mineral deposits in vitro. In addition, p-ERK1/2 levels were upregulated by FOXA1 silencing. Moreover, the increased osteogenic differentiation of FOXA1 knockdown hBMSCs was partially rescued by the addition of ERK1/2 signalling inhibitors. In a mouse model of femoral defects, a sheet of FOXA1-silencing BMSCs improved bone healing, as detected by microcomputed tomography and histological evaluation. Conclusion These findings collectively demonstrate that FOXA1 silencing promotes the osteogenic differentiation of BMSCs via the ERK1/2 signalling pathway, and silencing FOXA1 in vivo effectively promotes bone healing, suggesting that FOXA1 may be a novel target for bone healing.

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Mtu1 defects are correlated with reduced osteogenic differentiation

Cited by 7 publications

References 46 publications

Strategies for accelerating osteogenesis through nanoparticle-based DNA/mitochondrial damage repair

Strategies for accelerating osteogenesis through nanoparticle-based DNA/mitochondrial damage repair

Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities

Knockdown of FOXA1 enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells partly via activation of the ERK1/2 signalling pathway

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