Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis

Chen, Chider; Wang, Dandan; Moshaverinia, Alireza; Liu, Dawei; Kou, Xiaoxing; Yu, Wenjing; Yang, Ruili; Sun, Lingyun; Shi, Songtao

doi:10.1038/cr.2017.11

Cited by 100 publications

(93 citation statements)

References 67 publications

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“…BMMSCs can be regulated at both transcriptional and epigenetic levels in response to stimulation from various environmental elements 17 – 19 . BMMSC deficiency may contribute to bone degenerative phenotypes in osteopenia disease models 20 , 21 .…”

Section: Introductionmentioning

confidence: 99%

Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter

et al. 2018

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Ten-eleven translocation (Tet) family-mediated DNA oxidation represents an epigenetic modification capable of converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which regulates various biological processes. However, it is unknown whether Tet family affects mesenchymal stem cells (MSCs) or the skeletal system. Here we show that depletion of Tet1 and Tet2 results in impaired self-renewal and differentiation of bone marrow MSCs (BMMSCs) and a significant osteopenia phenotype. Tet1 and Tet2 deficiency reduces demethylation of the P2rX7 promoter and downregulates exosome release, leading to intracellular accumulation of miR-297a-5p, miR-297b-5p, and miR-297c-5p. These miRNAs inhibit Runx2 signaling to impair BMMSC function. We show that overexpression of P2rX7 rescues the impaired BMMSCs and osteoporotic phenotype in Tet1 and Tet2 double knockout mice. These results indicate that Tet1 and Tet2 play a critical role in maintaining BMMSC and bone homeostasis through demethylation of P2rX7 to control exosome and miRNA release. This Tet/P2rX7/Runx2 cascade may serve as a target for the development of novel therapies for osteopenia disorders.

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Section: Introductionmentioning

confidence: 99%

Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter

et al. 2018

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“…66 In addition, miR-151, a direct inhibitor of the mammalian target of rapamycin (mTOR) pathway, when transferred by MSC EVs, has been shown to ameliorate systemic sclerosis. 67 The natural origin of EVs, along with their high stability in the circulation, makes them ideal candidates for targeted therapy by efficient transfer of molecules upon engineering. 68 The strategy of engineering EVs with pro-regenerative molecules is currently gaining an increasing interest.…”

Section: Discussionmentioning

confidence: 99%

Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model

et al. 2020

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Acute kidney injury, defined by a rapid deterioration of renal function, is a common complication in hospitalized patients. Among the recent therapeutic options, the use of extracellular vesicles (EVs) is considered a promising strategy. Here we propose a possible therapeutic use of renal-derived EVs isolated from normal urine (urine-derived EVs [uEVs]) in a murine model of acute injury generated by glycerol injection. uEVs accelerated renal recovery, stimulating tubular cell proliferation, reducing the expression of inflammatory and injury markers, and restoring endogenous Klotho loss. When intravenously injected, labeled uEVs localized within injured kidneys and transferred their microRNA cargo. Moreover, uEVs contained the reno-protective Klotho molecule. Murine uEVs derived from Klotho null mice lost the reno-protective effect observed using murine EVs from wild-type mice. This was regained when Klotho-negative murine uEVs were reconstituted with recombinant Klotho. Similarly, ineffective fibroblast EVs acquired reno-protection when engineered with human recombinant Klotho. Our results reveal a novel potential use of uEVs as a new therapeutic strategy for acute kidney injury, highlighting the presence and role of the reno-protective factor Klotho.

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“…Primary bone marrow SSCs (BMSSCs) from female mice were prepared by flushing the femur/tibiae marrow cavity as previously described ( 14 ). Briefly, 15 × 10 6 cells were seeded in 100-mm dishes (Genesee Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, expansion of SSCs occurs early in the healing microenvironment ( 13 ), suggesting a possible interaction between SSCs and inflammatory cells. SSCs have demonstrated a potent immune-modulatory function in vitro and have been used to treat symptoms of inflammatory diseases ( 14 , 15 ). However, isolation and in vitro expansion of SSCs for transplantation use is artificial and does not accurately represent a potential in vivo function of SSCs.…”

Section: Introductionmentioning

confidence: 99%

Diabetes-Induced NF-κB Dysregulation in Skeletal Stem Cells Prevents Resolution of Inflammation

Syverson

Kralik

et al. 2019

Diabetes

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Type 1 diabetes (T1D) imposes a significant health burden by negatively affecting tissue regeneration during wound healing. The adverse effect of diabetes is attributed to high levels of inflammation, but the cellular mechanisms responsible remain elusive. In this study, we show that intrinsic skeletal stem cells (SSCs), a subset of mesenchymal stem cells, are essential for resolution of inflammation to occur during osseous healing by using genetic approaches to selectively ablate SSCs. T1D caused aberrant nuclear factor-κB (NF-κB) activation in SSCs and substantially enhanced inflammation in vivo. Constitutive or tamoxifen-induced inhibition of NF-κB in SSCs rescued the impact of diabetes on inflammation, SSC expansion, and tissue formation. In contrast, NF-κB inhibition in chondrocytes failed to reverse the effect of T1D. Mechanistically, diabetes caused defective proresolving macrophage (M2) polarization by reducing TGF-β1 expression by SSCs, which was recovered by NF-κB inhibition or exogenous TGF-β1 treatment. These data identify an underlying mechanism for altered healing in T1D and demonstrate that diabetes induces NF-κB hyperactivation in SSCs to disrupt their ability to modulate M2 polarization and resolve inflammation.

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Mesenchymal stem cell transplantation in tight-skin mice identifies miR-151-5p as a therapeutic target for systemic sclerosis

Cited by 100 publications

References 67 publications

Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter

Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter

Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model

Diabetes-Induced NF-κB Dysregulation in Skeletal Stem Cells Prevents Resolution of Inflammation

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