Monocytic Myeloid-Derived Suppressor Cells Inhibit Myofibroblastic Differentiation in Mesenchymal Stem Cells Through IL-15 Secretion

Cheuk, Yin Celeste; Xu, Shihao; Zhu, Dong; Luo, Yongsheng; Chen, Tian; Chen, Juntao; Li, Jiawei; Shi, Yi; Zhang, Yi; Rong, Ruiming

doi:10.3389/fcell.2022.817402

Cited by 7 publications

(2 citation statements)

References 35 publications

(39 reference statements)

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“…Similarly, BMMSCs were also used to treat brotic diseases, such as idiopathic pulmonary brosis, non-alcoholic fatty liver brosis, skin brosis and so on, due to the immunomodulatory function of BMMSCs to the recipient cells [34][35][36]. However, in recent years, researchers found that BMMSCs could differentiate into myo broblasts which is the key effector cell in brosis, in particular microenvironment including irradiation injury [37,38]. This brogenic differentiation phenomenon makes MSCs a potential danger to aggravate brosis stimulated by irradiation or other factors [39].…”

Section: Discussionmentioning

confidence: 99%

M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1

et al. 2023

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Purpose Radiotherapy is essential to cancer treatment, while it inevitably injures the surrounding normal tissues, and bone tissue is one of the most common sites prone to irradiation. Bone marrow mesenchymal stem cells (BMMSCs) are sensitive to irradiation and the irradiated dysfunction of BMMSCs may be closely related to irradiation-induced bone damage. Macropahges paly important role in stem cell function regulation, bone metabolic balance and irradiation response, but the effects of macrophages on irradiated BMMSCs are still unclear. This study aimed to investigate the role of macrophages and macrophage-derived exosomes in restoring irradiated BMMSCs function.Methods The effects of macrophage conditioned medium (CM) and macrophage-derived exosomes on osteogenic and brogenic differentiation capacities of irradiated BMMSCs were detected. The key microribonucleic acids (miRNAs) and targeted proteins in macrophage-derived exosomes were also determined. ResultsThe results showed that X-ray irradiation signi cantly inhibited the proliferation of BMMSCs.Additionally, it caused a differentiation imbalance of BMMSCs, with decreased osteogenic differentiation and increased brogenic differentiation. M2 macrophage-derived exosomes (M2D-exos) inhibited the brogenic differentiation and promoted the osteogenic differentiation of irradiated BMMSCs. We identi ed that miR-142-3p was signi cantly overexpressed in M2D-exos and irradiated BMMSCs treated with M2D-exos. After inhibition of miR-142-3p in M2 macrophage, the effects of M2D-exos on irradiated BMMSCs differentiation were eliminated. Furthermore, transforming growth factor beta 1 (TGF-β1), as a direct target of miR-142-3p, was signi cantly decreased in irradiated BMMSCs treated by M2D-exos. ConclusionThis study indicated that M2D-exos could carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1. These ndings pave the way for a new, promising, and cell-free therapeutic method to treat radiation-induced bone damage.

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Section: Discussionmentioning

confidence: 99%

M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1

et al. 2023

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“…The renal fibrosis model and MSC therapy scenario were utilized according to the previous studies [ 21 , 22 ]. C57BL/6 mice were divided into the following groups.…”

Section: Methodsmentioning

confidence: 99%

Periosteum-derived mesenchymal stem cell alleviates renal fibrosis through mTOR-mediated Treg differentiation

Luo

Zhang

et al. 2023

Renal Failure

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Background Mesenchymal stem cells (MSCs) are the hotspots of cellular therapy due to their low immunogenicity, potent immunoregulation, and unique renoprotection. The present study aimed to investigate the effects of periosteum-derived MSCs (PMSCs) in ischemia–reperfusion (IR)-mediated renal fibrosis. Methods Using cell proliferation assay, flow cytometry, immunofluorescence, and histologic analysis, the differences in cell characteristics, immunoregulation, and renoprotection of PMSCs were compared to the bone marrow-derived MSCs (BMSCs), the most frequently studied stem cells in cellular therapy. In addition, the mechanism of PMSC renoprotection was investigated by 5′ end of the RNA transcript sequencing (SMART-seq) and mTOR knockout mice. Results The proliferation and differentiation capabilities of PMSCs were stronger than those of BMSCs. Compared with BMSCs, the PMSCs exerted a better effect on alleviating renal fibrosis. Meanwhile, the PMSCs more effectively promote Treg differentiation. Treg exhaustion experiment indicated that Tregs exerted an important effect on inhibiting renal inflammation and acted as a critical mediator in PMSC renoprotection. Additionally, SMART-seq results implied that the PMSCs promoted Treg differentiation, possibly via the mTOR pathway. In vivo and in vitro experiments showed that PMSC inhibited mTOR phosphorylation of Treg. After mTOR knockout, the PMSCs failed to promote Treg differentiation. Conclusions Compared with BMSCs, the PMSCs exerted stronger immunoregulation and renoprotection that was mainly attributed to PMSC promotion for Treg differentiation by inhibiting the mTOR pathway.

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The role of immunosuppressive myofibroblasts in the aging process and age-related diseases

Salminen

2023

J Mol Med

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Tissue-resident fibroblasts are mesenchymal cells which control the structural integrity of the extracellular matrix (ECM). Fibroblasts possess a remarkable plasticity to allow them to adapt to the changes in the microenvironment and thus maintain tissue homeostasis. Several stresses, also those associated with the aging process, convert quiescent fibroblasts into myofibroblasts which not only display fibrogenic properties but also act as immune regulators cooperating both with tissue-resident immune cells and those immune cells recruited into affected tissues. TGF-β cytokine and reactive oxygen species (ROS) are major inducers of myofibroblast differentiation in pathological conditions either from quiescent fibroblasts or via transdifferentiation from certain other cell types, e.g., macrophages, adipocytes, pericytes, and endothelial cells. Intriguingly, TGF-β and ROS are also important signaling mediators between immunosuppressive cells, such as MDSCs, Tregs, and M2 macrophages. It seems that in pathological states, myofibroblasts are able to interact with the immunosuppressive network. There is clear evidence that a low-grade chronic inflammatory state in aging tissues is counteracted by activation of compensatory immunosuppression. Interestingly, common enhancers of the aging process, such as oxidative stress, loss of DNA integrity, and inflammatory insults, are inducers of myofibroblasts, whereas anti-aging treatments with metformin and rapamycin suppress the differentiation of myofibroblasts and thus prevent age-related tissue fibrosis. I will examine the reciprocal interactions between myofibroblasts and immunosuppressive cells within aging tissues. It seems that the differentiation of myofibroblasts with age-related harmful stresses enhances the activity of the immunosuppressive network which promotes tissue fibrosis and degeneration in elderly individuals.

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Monocytic Myeloid-Derived Suppressor Cells Inhibit Myofibroblastic Differentiation in Mesenchymal Stem Cells Through IL-15 Secretion

Cited by 7 publications

References 35 publications

M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1

M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1

Periosteum-derived mesenchymal stem cell alleviates renal fibrosis through mTOR-mediated Treg differentiation

The role of immunosuppressive myofibroblasts in the aging process and age-related diseases

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