Wnt/β-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients

Qi, Hanzhou; Ye, Yi-Ling; Suo, Yuan; Qu, Hong; Zhang, Haiyan; Yang, Kaibo; Zhang, Fan; Huang, Fen; Xuan, Li; Chen, Yanqiu; Jin, Hua; Liu, Qifa

doi:10.1038/s41419-021-03570-6

Cited by 4 publications

(2 citation statements)

References 49 publications

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“…For the downregulated DEGs, pathway enrichment analysis revealed that the graft-versus-host disease (GVHD) was significantly enriched. Qi et al [ 33 ] revealed that the adipogenic differentiation capacity was decreased in the active chronic GVHD MSCs compared with no-cGVHD MSCs. The adipogenesis of MSCs may be negatively associated with GVHD disease, which was in line with the results of the present study.…”

Section: Discussionmentioning

confidence: 99%

Screening for genes, miRNAs and transcription factors of adipogenic differentiation and dedifferentiation of mesenchymal stem cells

Ouyang

Dai

2023

J Orthop Surg Res

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Background The purpose of present study was to reveal the molecular mechanisms responsible for both adipogenic differentiation and dedifferentiation of mesenchymal stem cells (MSCs). Methods Microarray data GSE36923 were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between adipogenically differentiated cells vs undifferentiated bone marrow-derived MSCs, adipogenically differentiated cells vs dedifferentiated cells samples at day 7 and adipogenically differentiated cells vs dedifferentiated cells samples at day 35 were screened, and overlapped DEGs across the three groups were analyzed. The underlying functions of the upregulated and downregulated DEGs were investigated by Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis. The protein–protein interaction network was constructed, and hub genes were obtained subsequently. Hub genes were verified with GSE113253 dataset, and then miRNA-gene network and TF-gene network were constructed. Results A total of 284 upregulated DEGs and 376 downregulated DEGs overlapped across the three groups. PPAR signaling pathway, AMPK signaling pathway, insulin signaling pathway, carbon metabolism, pyruvate metabolism, fatty acid metabolism, regulation of lipolysis in adipocytes, biosynthesis of amino acids, citrate cycle (TCA cycle) and 2-Oxocarboxylic acid metabolism were the top 10 pathways involving in the upregulated DEGs, and graft-versus-host disease, allograft rejection, viral myocarditis, cell adhesion molecules, phagosome, type I diabetes mellitus, antigen processing and presentation, autoimmune thyroid disease, intestinal immune network for IgA production and rheumatoid arthritis were the top 10 pathways in downregulated DEGs. After validation, the 8 hub genes were IL6, PPARG, CCL2, FASN, CEBPA, ADIPOQ, FABP4 and LIPE. Ten key miRNAs were hsa-mir-27a-3p, hsa-mir-182-5p, hsa-mir-7-5p, hsa-mir-16-5p, hsa-mir-1-3p, hsa-mir-155-5p, hsa-mir-21-3p, hsa-mir-34a-5p, hsa-mir-27a-5p and hsa-mir-30c-5p, and 10 key TFs were TFDP1, GTF2A2, ZNF584, NRF1, ZNF512, NFRKB, CEBPG, KLF16, GLIS2 and MXD4. Conclusion Our study constructed miRNA-gene network and TF-gene network involved in both adipogenic differentiation and dedifferentiation of MSCs, contributing to enhancing the efficiency of MSCs transplantation in soft tissue defect repair and developing more potent remedies for adipogenesis-related skeletal disorders.

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Section: Discussionmentioning

confidence: 99%

Screening for genes, miRNAs and transcription factors of adipogenic differentiation and dedifferentiation of mesenchymal stem cells

Ouyang

Dai

2023

J Orthop Surg Res

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“…DKK3 has been reported to be secreted by MSCs, which have been shown to limit immune responses, including GVHD, by multiple soluble factors. Since DKK3 also regulates Wnt signaling ( 42 ), and Wnt/β-catenin signaling mediates increased osteogenic capacity and decreased adipogenic capacity in MSCs from patients with cGVHD MSCs ( 52 ), it is possible that DKK3 marks an early modulation of MSCs function toward a less regulatory phenotype. Thirdly, for alloreactive T cells to infiltrate target tissues, they have to migrate through the extracellular matrix (ECM).…”

Section: Discussionmentioning

confidence: 99%

Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death

Logan,

Fu,

Howard

et al. 2023

Journal of Clinical Investigation

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BACKGROUND Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT). More accurate information regarding the risk of developing cGVHD is required. Bone marrow (BM) grafts contribute to lower cGVHD, which creates a dispute over whether risk biomarker scores should be used for peripheral blood (PB) and BM. METHODS Day 90 plasma proteomics from PB and BM recipients developing cGVHD revealed 5 risk markers that were added to 8 previous cGVHD markers to screen 982 HCT samples of 2 multicenter Blood and Marrow Transplant Clinical Trials Network (BMTCTN) cohorts. Each marker was tested for its association with cause-specific hazard ratios (HRs) of cGVHD using Cox-proportional-hazards models. We paired these clinical studies with biomarker measurements in a mouse model of cGVHD. RESULTS Spearman correlations between DKK3 and MMP3 were significant in both cohorts. In BMTCTN 0201 multivariate analyses, PB recipients with 1-log increase in CXCL9 and DKK3 were 1.3 times (95% CI: 1.1–1.4, P = 0.001) and 1.9 times (95%CI: 1.1–3.2, P = 0.019) and BM recipients with 1-log increase in CXCL10 and MMP3 were 1.3 times (95%CI: 1.0–1.6, P = 0.018 and P = 0.023) more likely to develop cGVHD. In BMTCTN 1202, PB patients with high CXCL9 and MMP3 were 1.1 times (95%CI: 1.0–1.2, P = 0.037) and 1.2 times (95%CI: 1.0–1.3, P = 0.009) more likely to develop cGVHD. PB patients with high biomarkers had increased likelihood to develop cGVHD in both cohorts (22%–32% versus 8%–12%, P = 0.002 and P < 0.001, respectively). Mice showed elevated circulating biomarkers before the signs of cGVHD. CONCLUSION Biomarker levels at 3 months after HCT identify patients at risk for cGVHD occurrence. FUNDING NIH grants R01CA168814, R21HL139934, P01CA158505, T32AI007313, and R01CA264921.

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A novel type of mesenchymal stem cells derived from bovine metanephric mesenchyme

Wang¹,

Wu²,

Liu³

et al. 2022

Tissue and Cell

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Wnt/β-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients

Cited by 4 publications

References 49 publications

Screening for genes, miRNAs and transcription factors of adipogenic differentiation and dedifferentiation of mesenchymal stem cells

Screening for genes, miRNAs and transcription factors of adipogenic differentiation and dedifferentiation of mesenchymal stem cells

Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death

A novel type of mesenchymal stem cells derived from bovine metanephric mesenchyme

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