Similar Datasets
Project description:Intramuscular fatty deposits, which are seen in muscular dystrophies and with aging, negatively affect muscle function. The cells of origin of adipocytes constituting these fatty deposits are mesenchymal stromal cells, fibroadipogenic progenitors (FAPs). We uncover a molecular fate switch, involving miR-206 and the transcription factor Runx1, that controls FAP differentiation to adipocytes. Mice deficient in miR-206 exhibit increased adipogenesis following muscle injury. Adipogenic differentiation of FAPs is abrogated by miR-206 mimics. Using a labeled microRNA (miRNA) pull-down and sequencing (LAMP-seq), we identified Runx1 as a miR-206 target, with miR-206 repressing Runx1 translation. In the absence of miR-206 in FAPs, Runx1 occupancy near transcriptional start sites of adipogenic genes and expression of these genes increase. We demonstrate that miR-206 mimicry in vivo limits intramuscular fatty infiltration. Our results provide insight into the underlying molecular mechanisms of FAP fate determination and formation of harmful fatty deposits in skeletal muscle.
| S-EPMC8254802 | biostudies-literature
Project description:Targeting microRNA-mediated gene repression limits the adipogenic conversion of skeletal muscle mesenchymal stromal cells
| PRJNA719816 | ENA
Project description:Peripheral arterial disease (PAD) is associated with lower-extremity muscle wasting. Hallmark features of PAD-associated skeletal muscle pathology include loss of skeletal muscle mass, reduced strength and physical performance, increased inflammation, fibrosis, and adipocyte infiltration. At the molecular level, skeletal muscle ischemia has also been associated with gene and microRNA (miRNA) dysregulation. Mesenchymal stromal cells (MSCs) have been shown to enhance muscle regeneration and improve muscle function in various skeletal muscle injuries. This study aimed to evaluate the effects of intramuscularly delivered human umbilical cord-derived MSCs (hUC-MSCs) on skeletal muscle ischemia. Herein, we report an hUC-MSC-mediated amelioration of ischemia-induced skeletal muscle atrophy and function via enhancement of myofiber regeneration, reduction of tissue inflammation, adipocyte accumulation, and tissue fibrosis. These changes were observed in the absence of cell-mediated enhancement of blood flow recovery as measured by laser Doppler imaging. Furthermore, reduced tissue fibrosis in the hUC-MSC-treated group was associated with upregulation of miR-1, miR-133a, and miR-29b and downregulation of targeted pro-fibrotic genes such as Col1a1 and Fn1. Our results support the use of hUC-MSCs as a novel approach to reduce fibrosis and promote skeletal muscle regeneration after ischemic injury in patients with PAD.
| S-EPMC11541228 | biostudies-literature
Project description:Mechanisms mediating mesenchymal stromal/stem cells' (MSCs) multipotency are unclear. Although the expression of the pluripotency factor OCT4 has been detected in MSCs, whether it has a functional role in adult stem cells is still controversial. We hypothesized that a physiological expression level of OCT4 is important to regulate MSCs' multipotency and trigger differentiation in response to environmental signals. Here, we specifically suppressed OCT4 in MSCs by using siRNA technology before directed differentiation. OCT4 expression levels were reduced by 82% in siOCT4-MSCs, compared with controls. Interestingly, siOCT4-MSCs also presented a hypermethylated OCT4 promoter. OCT4 silencing significantly impaired the ability of MSCs to differentiate into osteoblasts. Histologic and macroscopic analysis showed a lower degree of mineralization in siOCT4-MSCs than in controls. Moreover, OCT4 silencing prevented the up-regulation of osteoblast lineage-associated genes during differentiation. Similarly, OCT4 silencing resulted in decreased MSC differentiation potential towards the adipogenic lineage. The accumulation of lipids was reduced 3.0-fold in siOCT4-MSCs, compared with controls. The up-regulation of genes engaged in the early stages of adipogenesis was also suppressed in siOCT4-MSCs. Our findings provide evidence of a functional role for OCT4 in MSCs and indicate that a basal expression of this transcription factor is essential for their multipotent capacity.
| S-EPMC6651015 | biostudies-literature
Project description:Peripheral nerve injury can lead to progressive muscle atrophy and poor motor function recovery, which is a difficult point of treatment, and the mechanism needs to be further explored. In previous studies, we found that miR-142a-3p was significantly upregulated and persistently highly expressed in denervated mouse skeletal muscle. Here, we show that overexpression of miR-142a-3p inhibited the growth and differentiation of C2C12 myoblast, while knockdown of miR-142a-3p had a promoting effect. In vitro, knockdown of miR-142a-3p in denervated mouse skeletal muscle effectively increased proliferating muscle satellite cells and ameliorated muscle atrophy. Mechanistically, the myoregulator Mef2a was proved to be an important downstream target of miR-142a-3p, and miR-142a-3p regulates skeletal muscle differentiation and regeneration by inhibiting the expression of Mef2a. The co-knockdown of Mef2a and miR-142a-3p effectively alleviated or offset the biological effects of miR-142a-3p knockdown. In conclusion, our data revealed that miR-142a-3p regulates neurogenic skeletal muscle atrophy by targeting Mef2a.
| S-EPMC10362021 | biostudies-literature
Project description:Mesenchymal stromal cells (MSCs) are multipotent cells found in different tissues: bone marrow, peripheral blood, adipose tissues, skeletal muscle, perinatal tissues, and dental pulp. MSCs are able to self-renew and to differentiate into multiple lineages, and they have been extensively used for cell therapy mostly owing to their anti-fibrotic and immunoregulatory properties that have been suggested to be at the basis for their regenerative capability. MSCs exert their effects by releasing a variety of biologically active molecules such as growth factors, chemokines, and cytokines, either as soluble proteins or enclosed in extracellular vesicles (EVs). Analyses of MSC-derived secretome and in particular studies on EVs are attracting great attention from a medical point of view due to their ability to mimic all the therapeutic effects produced by the MSCs (i.e., endogenous tissue repair and regulation of the immune system). MSC-EVs could be advantageous compared with the parental cells because of their specific cargo containing mRNAs, miRNAs, and proteins that can be biologically transferred to recipient cells. MSC-EV storage, transfer, and production are easier; and their administration is also safer than MSC therapy. The skeletal muscle is a very adaptive tissue, but its regenerative potential is altered during acute and chronic conditions. Recent works demonstrate that both MSCs and their secretome are able to help myofiber regeneration enhancing myogenesis and, interestingly, can be manipulated as a novel strategy for therapeutic interventions in muscular diseases like muscular dystrophies or atrophy. In particular, MSC-EVs represent promising candidates for cell free-based muscle regeneration. In this review, we aim to give a complete picture of the therapeutic properties and advantages of MSCs and their products (MSC-derived EVs and secreted factors) relevant for skeletal muscle regeneration in main muscular diseases.
| S-EPMC8172230 | biostudies-literature
Project description:The necessity of mesenchymal stromal cells, called fibroadipogenic progenitors (FAPs), in skeletal muscle regeneration and maintenance remains unestablished. We report the generation of a PDGFRαCreER knockin mouse model that provides a specific means of labeling and targeting FAPs. Depletion of FAPs using Cre-dependent diphtheria toxin expression results in loss of expansion of muscle stem cells (MuSCs) and CD45+ hematopoietic cells after injury and impaired skeletal muscle regeneration. Furthermore, FAP-depleted mice under homeostatic conditions exhibit muscle atrophy and loss of MuSCs, revealing that FAPs are required for the maintenance of both skeletal muscle and the MuSC pool. We also report that local tamoxifen metabolite delivery to target CreER activity in a single muscle, removing potentially confounding systemic effects of ablating PDGFRα+ cells distantly, also causes muscle atrophy. These data establish a critical role of FAPs in skeletal muscle regeneration and maintenance.
| S-EPMC7034941 | biostudies-literature
Project description:PURPOSE:Adipogenic differentiation of adipose tissue-derived mesenchymal stem cells (AMSCs) is critical to many disease-related disorders, such as obesity and diabetes. Studies have demonstrated that miRNA-138 (miR-138) is closely involved in adipogenesis. However, the mechanisms affected by miR-138 remain unclear. This work aimed to investigate interactions between miR-138 and lipoprotein lipase (LPL), a key lipogenic enzyme, in AMSCs. MATERIALS AND METHODS:Human AMSCs (hAMSCs) isolated from human abdomen tissue were subjected to adipogenic differentiation medium. Quantitative real-time polymerase chain reaction and Western blot assay were applied to measure the expressions of miR-138, LPL, and the two adipogenic transcription factors cytidine-cytidine-adenosine-adenosine-thymidine enhancer binding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ). The relationship between miR-138 and LPL was predicted utilizing the miRTarBase database and validated by dual luciferase reporter assay. RESULTS:Showing increases in C/EBPα and PPARγ expression levels, hAMSCs were induced into adipogenic differentiation. During adipogenesis of hAMSCs, miR-138 expression was significantly downregulated. Overexpression of miR-138 by transfection inhibited hAMSCs adipogenic differentiation in vitro. Mechanically, LPL was a target of miR-138. LPL expression was upregulated during adipogenesis of hAMSCs, and this upregulation was reversed by miR-138 overexpression. Functionally, silencing of LPL by transfection exerted similar inhibition of the expressions of C/EBPα and PPARγ. Meanwhile, LPL ectopic expression was able to partly abolish the suppressive effect of miR-138 overexpression on adipogenic differentiation of hAMSCs. CONCLUSION:Upregulation of miR-138 inhibits adipogenic differentiation of hAMSCs by directly downregulating LPL.
| S-EPMC6881710 | biostudies-literature
Project description:Mesenchymal stromal cell (MSC) senescence is a key factor in skeletal aging, affecting the potential of MSC applications. Identifying targets to prevent MSC and skeletal senescence is crucial. Here, we report increased miR-29 expression in bone tissues of aged mice, osteoporotic patients, and senescent MSCs. Genetic overexpression of miR-29 in Prx1-positive MSCs significantly accelerates skeletal senescence, reducing cortical bone thickness and trabecular bone mass, while increasing femur cross-sectional area, bone marrow adiposity, p53, and senescence-associated secretory phenotype (SASP) levels. Mechanistically, miR-29 promotes senescence by upregulating p53 via targeting Kindlin-2 mRNA. miR-29 knockdown in BMSCs impedes skeletal senescence, enhances bone mass, and accelerates calvarial defect regeneration, also reducing lipopolysaccharide (LPS)-induced organ injuries and mortality. Thus, our findings underscore miR-29 as a promising therapeutic target for senescence-related skeletal diseases and acute inflammation-induced organ damage.
| S-EPMC11384963 | biostudies-literature
Project description:Advances in the engineering of comprehensive skeletal muscle models in vitro will improve drug screening platforms and can lead to better therapeutic approaches for the treatment of skeletal muscle injuries. To this end, a vascularized tissue-engineered skeletal muscle (TE-SkM) model that includes adipocytes was developed to better emulate the intramuscular adipose tissue that is observed in skeletal muscles of patients with diseases such as diabetes. Muscle precursor cells cultured with and without microvessels derived from adipose tissue (microvascular fragments) were used to generate TE-SkM constructs, with and without a microvasculature, respectively. TE-SkM constructs were treated with adipogenic induction media to induce varying levels of adipogenesis. With a delayed addition of induction media to allow for angiogenesis, a robust microvasculature in conjunction with an increased content of adipocytes was achieved. The augmentation of vascularized TE-SkM constructs with adipocytes caused a reduction in maturation (compaction), mechanical integrity (Young's modulus), and myotube and vessel alignment. An increase in basal glucose uptake was observed in both levels of adipogenic induction, and a diminished insulin-stimulated glucose uptake was associated with the higher level of adipogenic differentiation and the greater number of adipocytes.
| S-EPMC8812504 | biostudies-literature