scholarly journals Galectin-3 promotes the adipogenic differentiation of PDGFRα+ cells and ectopic fat formation in regenerating muscle

Development ◽  
2022 ◽  
Author(s):  
Naoki Takada ◽  
Masaki Takasugi ◽  
Yoshiki Nonaka ◽  
Tomonori Kamiya ◽  
Kazuaki Takemura ◽  
...  
Keyword(s):  
Cell Population ◽  
Muscle Regeneration ◽  
Adipogenic Differentiation ◽  
Mesenchymal Progenitors ◽  
Intermuscular Adipose Tissue ◽  
Pathological Conditions ◽  
Promising Target ◽  
Galectin 3 ◽  
Prevalence Of Obesity ◽  
Lifestyle Related Diseases

Worldwide prevalence of obesity is associated with the increase of lifestyle-related diseases. The accumulation of intermuscular adipose tissue (IMAT) is considered a major problem whereby obesity leads to sarcopenia and metabolic disorders and thus is a promising target for treating these pathological conditions. However, whereas obesity-associated IMAT is suggested to originate from PDGFRα+ mesenchymal progenitors, processes underlying their adipogenesis remain largely unexplored. Here, we comprehensively investigated intra- and extracellular changes associated with these processes using single-cell RNA sequencing (scRNA-Seq) and mass spectrometry. Our scRNA-Seq analysis identified a small PDGFRα+ cell population in obese mice directed strongly toward adipogenesis. Proteomic analysis showed that the appearance of this cell population is accompanied by an increase in galectin-3 in interstitial environments, which was found to activate adipogenic PPARγ signals in PDGFRα+ cells. Moreover, IMAT formation during muscle regeneration was significantly suppressed in galectin-3 KO mice. Our findings, together with these multi-omics datasets, could unravel microenvironmental networks during muscle regeneration highlighting possible therapeutic targets against IMAT formation in obesity.

The origin of intermuscular adipose tissue and its pathophysiological implications

2009 ◽  
Vol 297 (5) ◽  
pp. E987-E998 ◽  
Author(s):  
Roberto Vettor ◽  
Gabriella Milan ◽  
Chiara Franzin ◽  
Marta Sanna ◽  
Paolo De Coppi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Metabolic Diseases ◽  
High Plasma ◽  
Stem Cell Population ◽  
Phenotypic Switch ◽  
Mesenchymal Progenitors ◽  
Intermuscular Adipose Tissue ◽  
Pathological Conditions ◽  
Age Related ◽  
Mitochondrial Ros

The intermuscular adipose tissue (IMAT) is a depot of adipocytes located between muscle bundles. Several investigations have recently been carried out to define the phenotype, the functional characteristics, and the origin of the adipocytes present in this depot. Among the different mechanisms that could be responsible for the accumulation of fat in this site, the dysdifferentiation of muscle-derived stem cells or other mesenchymal progenitors has been postulated, turning them into cells with an adipocyte phenotype. In particular, muscle satellite cells (SCs), a heterogeneous stem cell population characterized by plasticity and self-renewal that allow muscular growth and regeneration, can acquire features of adipocytes, including the abilities to express adipocyte-specific genes and accumulate lipids. Failure to express the transcription factors that direct mesenchymal precursors into fully differentiated functionally specialized cells may be responsible for their phenotypic switch into the adipogenic lineage. We proved that human SCs also possess a clear adipogenic potential that could explain the presence of mature adipocytes within skeletal muscle. This occurs under some pathological conditions (i.e., primary myodystrophies, obesity, hyperglycemia, high plasma free fatty acids, hypoxia, etc.) or as a consequence of thiazolidinedione treatment or simply because of a sedentary lifestyle or during aging. Several pathways and factors (PPARs, WNT growth factors, myokines, GEF-GAP-Rho, p66shc, mitochondrial ROS production, PKCβ) could be implicated in the adipogenic conversion of SCs. The understanding of the molecular pathways that regulate muscle-to-fat conversion and SC behavior could explain the increase in IMAT depots that characterize many metabolic diseases and age-related sarcopenia.

scholarly journals Characterization of the Skeletal Muscle Secretome Reveals a Role for Extracellular Vesicles and IL1α/IL1β in Restricting Fibro/Adipogenic Progenitor Adipogenesis

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1171
Author(s):  
Simone Vumbaca ◽  
Giulio Giuliani ◽  
Valeria Fiorentini ◽  
Flavia Tortolici ◽  
Andrea Cerquone Perpetuini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Fate ◽  
Extracellular Vesicles ◽  
Muscle Regeneration ◽  
Adipogenic Differentiation ◽  
Control Cell ◽  
Regeneration Process ◽  
Adult Skeletal Muscle ◽  
Pathological Conditions ◽  
Cell Cell

Repeated mechanical stress causes injuries in the adult skeletal muscle that need to be repaired. Although muscle regeneration is a highly efficient process, it fails in some pathological conditions, compromising tissue functionality. This may be caused by aberrant cell–cell communication, resulting in the deposition of fibrotic and adipose infiltrates. Here, we investigate in vivo changes in the profile of skeletal muscle secretome during the regeneration process to suggest new targetable regulatory circuits whose failure may lead to tissue degeneration in pathological conditions. We describe the kinetic variation of expression levels of 76 secreted proteins during the regeneration process. In addition, we profile the gene expression of immune cells, endothelial cells, satellite cells, and fibro-adipogenic progenitors. This analysis allowed us to annotate each cell-type with the cytokines and receptors they have the potential to synthetize, thus making it possible to draw a cell–cell interaction map. We next selected 12 cytokines whose receptors are expressed in FAPs and tested their ability to modulate FAP adipogenesis and proliferation. We observed that IL1α and IL1β potently inhibit FAP adipogenesis, while EGF and BTC notably promote FAP proliferation. In addition, we characterized the cross-talk mediated by extracellular vesicles (EVs). We first monitored the modulation of muscle EV cargo during tissue regeneration. Using a single-vesicle flow cytometry approach, we observed that EVs differentially affect the uptake of RNA and proteins into their lumen. We also investigated the EV capability to interact with SCs and FAPs and to modulate their proliferation and differentiation. We conclude that both cytokines and EVs secreted during muscle regeneration have the potential to modulate adipogenic differentiation of FAPs. The results of our approach provide a system-wide picture of mechanisms that control cell fate during the regeneration process in the muscle niche.

scholarly journals Amidation-Modified Apelin-13 Regulates PPARγ and Perilipin to Inhibit Adipogenic Differentiation and Promote Lipolysis

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Sha Wang ◽  
Guoying Gao ◽  
Yiwei He ◽  
Qiong Li ◽  
Zhan Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Adipogenic Differentiation ◽  
Animal Experiments ◽  
Endocrine System ◽  
Average Diameter ◽  
Lifestyle Changes ◽  
Biologically Active ◽  
Regulation Mechanism ◽  
Prevalence Of Obesity

With the adjustment of human diet and lifestyle changes, the prevalence of obesity is increasing year by year. Obesity is closely related to the excessive accumulation of white adipose tissue (WAT), which can synthesize and secrete a variety of adipokines. Apelin is a biologically active peptide in the adipokines family. Past studies have shown that apelin plays an important regulatory role in the pathogenesis and pathophysiology of diseases such as the cardiovascular system, respiratory system, digestive system, nervous system, and endocrine system. Apelin is also closely related to diabetes and obesity. Therefore, we anticipate that apelin-13 has an effect on lipometabolism and intend to explore the effect of apelin-13 on lipometabolism at the cellular and animal levels. In in vitro experiments, amidation-modified apelin-13 can significantly reduce the lipid content; TG content; and the expression of PPARγ, perilipin mRNA, and protein in adipocytes. Animal experiments also show that amidation modification apelin-13 can improve the abnormal biochemical indicators of diet-induced obesity (DOI) rats and can reduce the average diameter of adipocytes in adipose tissue, the concentration of glycerol, and the expression of PPARγ and perilipin mRNA and protein. Our results show that apelin-13 can affect the metabolism of adipose tissue, inhibit adipogenic differentiation of adipocytes, promote lipolysis, and thereby improve obesity. The mechanism may be regulating the expression of PPARγ to inhibit adipogenic differentiation and regulating the expression of perilipin to promote lipolysis. This study helps us understand the role of apelin-13 in adipose tissue and provide a basis for the elucidation of the regulation mechanism of lipometabolism and the development of antiobesity drugs.

Scaffold biomaterials and nano-based therapeutic strategies for skeletal muscle regeneration

Nanomedicine ◽  
2021 ◽  
Author(s):  
Franco Tacchi ◽  
Josué Orozco-Aguilar ◽  
Danae Gutiérrez ◽  
Felipe Simon ◽  
Javier Salazar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Genetic Diseases ◽  
Therapeutic Strategies ◽  
Skeletal Muscle Regeneration ◽  
Cell Printing ◽  
Strength Recovery ◽  
Pathological Conditions ◽  
Therapeutic Alternatives ◽  
Hybrid Biomaterials

Skeletal muscle is integral to the functioning of the human body. Several pathological conditions, such as trauma (primary lesion) or genetic diseases such as Duchenne muscular dystrophy (DMD), can affect and impair its functions or exceed its regeneration capacity. Tissue engineering (TE) based on natural, synthetic and hybrid biomaterials provides a robust platform for developing scaffolds that promote skeletal muscle regeneration, strength recovery, vascularization and innervation. Recent 3D-cell printing technology and the use of nanocarriers for the release of drugs, peptides and antisense oligonucleotides support unique therapeutic alternatives. Here, the authors present recent advances in scaffold biomaterials and nano-based therapeutic strategies for skeletal muscle regeneration and perspectives for future endeavors.

scholarly journals Tsc2 disruption in mesenchymal progenitors results in tumors with vascular anomalies overexpressing Lgals3

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Peter J Klover ◽  
Rajesh L Thangapazham ◽  
Jiro Kato ◽  
Ji-an Wang ◽  
Stasia A Anderson ◽  
...  
Keyword(s):  
Lung Function ◽  
Tuberous Sclerosis Complex ◽  
Serum Levels ◽  
Limb Bud ◽  
Mesenchymal Progenitors ◽  
Expression Signature ◽  
Mtorc1 Signaling ◽  
Impaired Lung Function ◽  
Galectin 3

Increased mTORC1 signaling from TSC1/TSC2 inactivation is found in cancer and causes tuberous sclerosis complex (TSC). The role of mesenchymal-derived cells in TSC tumorigenesis was investigated through disruption of Tsc2 in craniofacial and limb bud mesenchymal progenitors. Tsc2cKOPrrx1-cre mice had shortened lifespans and extensive hamartomas containing abnormal tortuous, dilated vessels prominent in the forelimbs. Abnormalities were blocked by the mTORC1 inhibitor sirolimus. A Tsc2/mTORC1 expression signature identified in Tsc2-deficient fibroblasts was also increased in bladder cancers with TSC1/TSC2 mutations in the TCGA database. Signature component Lgals3 encoding galectin-3 was increased in Tsc2-deficient cells and serum of Tsc2cKOPrrx1-cre mice. Galectin-3 was increased in TSC-related skin tumors, angiomyolipomas, and lymphangioleiomyomatosis with serum levels in patients with lymphangioleiomyomatosis correlating with impaired lung function and angiomyolipoma presence. Our results demonstrate Tsc2-deficient mesenchymal progenitors cause aberrant morphogenic signals, and identify an expression signature including Lgals3 relevant for human disease of TSC1/TSC2 inactivation and mTORC1 hyperactivity.

scholarly journals Role of Overweight and Obesity in Gastrointestinal Disease

Nutrients ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 111 ◽  
Author(s):  
Sara Emerenziani ◽  
Michele Pier Luca Guarino ◽  
Laura Trillo Asensio ◽  
Annamaria Altomare ◽  
Mentore Ribolsi ◽  
...  
Keyword(s):  
Potential Role ◽  
Gastrointestinal Disease ◽  
Overweight And Obesity ◽  
Biological Mechanisms ◽  
Pathological Conditions ◽  
Severe Impairment ◽  
Prevalence Of Obesity ◽  
Inflammatory Bowel ◽  
Overall Mortality

The prevalence of obesity is increasing worldwide, leading to a severe impairment of overall health. Actually, obesity has been associated with several pathological conditions, causing an excess overall mortality. In particular, overweight and obesity are well known risk factors for a variety of gastrointestinal (GI) disorders i.e., functional GI disorders as well as, inflammatory bowel disease (IBD), pancreatitis, and GI cancer. The aim of the present review is to summarize the potential role of overweight and obesity in GI disease with particular focus on plausible biological mechanisms that could explain the association between obesity and GI disease based on the most recent evidence in the literature.

scholarly journals Mesenchymal Progenitors Derived from Different Locations in Long Bones Display Diverse Characteristics

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Weiguang Lu ◽  
Bo Gao ◽  
Jing Fan ◽  
Pengzhen Cheng ◽  
Yaqian Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adipogenic Differentiation ◽  
Osteoclast Formation ◽  
Long Bones ◽  
Differentiation Potential ◽  
Mesenchymal Progenitors ◽  
Multiple Differentiation ◽  
Osteoclastic Differentiation ◽  
Proliferation Assays

Mesenchymal progenitors within bone marrow have multiple differentiation potential and play an essential role in the maintenance of adult skeleton homeostasis. Mesenchymal progenitors located in bone regions other than the bone marrow also display bone-forming properties. However, owing to the differences in each distinct microenvironment, the mesenchymal characteristics of skeletal progenitor cells within different regions of long bones may show some differences. In order to clearly elucidate these differences, we performed a comparative study on mesenchymal progenitors from different regions of long bones. Here, we isolated mesenchymal progenitors from the periosteum, endosteum, and bone marrow of rat long bones. The three groups exhibited similar cellular morphologies and expressed the typical surface markers associated with mesenchymal stem cells. Interestingly, after cell proliferation assays and bidirectional differentiation analysis, periosteal mesenchymal progenitors showed a higher proliferative ability and adipogenic differentiation potential. In contrast, endosteal mesenchymal progenitors were more prone to osteogenic differentiation. Using in vitro osteoclast culture systems, conditioned media from different mesenchymal progenitor cultures were used to induce osteoclastic differentiation. Osteoclast formation was found to be significantly promoted by the secretion of RANKL and IL-6 by endosteal progenitors. Overall, our results provide strong evidence for the importance of selecting the appropriate source of skeletal progenitors for applications in future skeleton regeneration therapies.

scholarly journals Galectin-3: Roles in Neurodevelopment, Neuroinflammation, and Behavior

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 798
Author(s):  
Ivan Srejovic ◽  
Dragica Selakovic ◽  
Nemanja Jovicic ◽  
Vladimir Jakovljević ◽  
Miodrag L. Lukic ◽  
...  
Keyword(s):  
Nervous System ◽  
Glial Cells ◽  
Mammalian Cells ◽  
Protective Role ◽  
Target Cells ◽  
Adult Mice ◽  
Pathological Conditions ◽  
Apoptotic Effect ◽  
Galectin 3 ◽  
The Central Nervous System

There is a plethora of evidence to suggest that Galectin-3 plays an important role in normal functions of mammalian cells, as well as in different pathogenic conditions. This review highlights recent data published by researchers, including our own team, on roles of Galectin-3 in the nervous system. Here, we discuss the roles of Galectin-3 in brain development, its roles in glial cells, as well as the interactions of glial cells with other neural and invading cells in pathological conditions. Galectin-3 plays an important role in the pathogenesis of neuroinflammatory and neurodegenerative disorders, such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. On the other hand, there is also evidence of the protective role of Galectin-3 due to its anti-apoptotic effect in target cells. Interestingly, genetic deletion of Galectin-3 affects behavioral patterns in maturing and adult mice. The results reviewed in this paper and recent development of highly specific inhibitors suggests that Galectin-3 may be an important therapeutic target in pathological conditions including the disorders of the central nervous system.

Rad is temporally regulated within myogenic progenitor cells during skeletal muscle regeneration

2006 ◽  
Vol 290 (2) ◽  
pp. C379-C387 ◽  
Author(s):  
Thomas J. Hawke ◽  
Shane B. Kanatous ◽  
Cindy M. Martin ◽  
Sean C. Goetsch ◽  
Daniel J. Garry
Keyword(s):  
Skeletal Muscle ◽  
Progenitor Cells ◽  
Cell Population ◽  
Muscle Regeneration ◽  
Progenitor Cell ◽  
Transcriptional Activity ◽  
Skeletal Muscle Regeneration ◽  
Progenitor Cell Population ◽  
Myogenic Progenitor Cells ◽  
Myogenic Progenitor

The successful use of myogenic progenitor cells for therapeutic applications requires an understanding of the intrinsic and extrinsic cues involved in their regulation. Herein we demonstrate the expression pattern and transcriptional regulation of Rad, a prototypical member of a family of novel Ras-related GTPases, during mammalian development and skeletal muscle regeneration. Rad was identified using microarray analysis, which revealed robust upregulation of its expression during skeletal muscle regeneration. Our current findings demonstrate negligible Rad expression with resting adult skeletal muscle; however, after muscle injury, Rad is expressed within the myogenic progenitor cell population. Rad expression is significantly increased and localized to the myogenic progenitor cell population during the early phases of regeneration and within the newly regenerated myofibers during the later phases of regeneration. Immunohistochemical analysis demonstrated that Rad and MyoD are coexpressed within the myogenic progenitor cell population of regenerating skeletal muscle. This expression profile of Rad during skeletal muscle regeneration is consistent with the proposed roles for Rad in the inhibition of L-type Ca2+channel activity and the inhibition of Rho/RhoA kinase activity. We also have demonstrated that known myogenic transcription factors (MEF2, MyoD, and Myf-5) can increase the transcriptional activity of the Rad promoter and that this ability is significantly enhanced by the presence of the Ca2+-dependent phosphatase calcineurin. Furthermore, this enhanced transcriptional activity appears to be dependent on the presence of a conserved NFAT binding motif within the Rad promoter. Taken together, these data define Rad as a novel factor within the myogenic progenitor cells of skeletal muscle and identify key regulators of its transcriptional activity.

scholarly journals Bone Marrow Macrophage Galectin-3 Regulates Platelet Production through Recognition of O-Glycans on Megakaryocytes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 409-409
Author(s):  
Melissa M Lee-Sundlov ◽  
Renata Grozovsky ◽  
Silvia Giannini ◽  
Martina McGrath ◽  
Haley E Ramsey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antigen Expression ◽  
Blood Platelet ◽  
Activated Macrophages ◽  
Bone Marrow Macrophage ◽  
Platelet Production ◽  
Platelet Counts ◽  
Pathological Conditions ◽  
Galectin 3

Abstract Bone marrow (BM) macrophages maintain both survival and retention of hematopoietic stem cells and regulate erythropoiesis. The role of macrophage lectins and glycans in thrombopoiesis remains unclear. We report a novel role for bone marrow macrophage galectin-3 in maintaining platelet counts, by phagocytosing megakaryocytes (MKs) expressing the Thomsen-Friedenreich (TF) antigen, which is often exposed under pathological conditions, such as cancer and malignancies. The TF antigen is a disaccharide presented in cryptic form on O-glycans and covered by a sialic acid moiety. The sialyltransferase ST3Gal1 transfers sialic acid onto the TF antigen. To investigate the role of O-glycans in thrombopoiesis, we generated mice with increased TF antigen in MKs by generating St3gal1loxP/PF4+ mice specifically lacking ST3Gal1 in the MK lineage. As expected, St3gal1loxP/PF4+ circulating platelets and BM MKs had increased TF antigen expression, compared to controls, as evidenced by peanut agglutinin (PNA) binding. Other blood cell lineages had no increase in TF antigen expression. St3gal1loxP/PF4+ mice developed mild thrombocytopenia, but surprisingly had virtually normal platelet clearance. BM MK colony forming units and in vitro proplatelet production were normal in St3gal1loxP/PF4+ mice, suggesting that extrinsic factors in the St3gal1loxP/PF4+BM environment affected platelet production. St3gal1loxP/PF4+ BM smears revealed increased hemophagocytosis, indicative of an increase in phagocytic macrophages. In vivo macrophage ablation by injection of clodronate-encapsulated liposomes significantly reduced the numbers of activated macrophages, thereby normalizing blood platelet counts and size. Flow cytometric phenotypic analysis of BM-derived macrophages showed an increased population of activated macrophages in St3gal1loxP/PF4+ mice, compared to controls, specifically macrophages with increased galectin-3 expression, a ligand for the TF antigen. Immunofluorescence staining of BM sections using a specific antibody towards the TF antigen showed that MK progenitors and pro-platelet-like structures expressed TF antigen in control BMs, which is significantly increased in St3gal1loxP/PF4+ mice and co-localized with galectin-3 expressing macrophages, supporting the notion that MK O-glycans and macrophage galectin-3 play a role in thrombopoiesis under steady state and pathological conditions. Consistent with this notion, galectin-3 deficient mice have slightly, but significantly increased blood platelet counts. We conclude that galactin-3 plays a minor role in normal thrombopoiesis. Activation of galectin-3 expressing macrophages by the MK TF antigen leads to MK phagocytosis, inhibition of platelet formation and thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

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