Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells

Yang, Jiekun; Vamvini, Maria; Nigro, Pasquale; Ho, Li‐Lun; Galani, Kyriaki; Alvarez, Marcus; Tanigawa, Yosuke; Renfro, Ashley; Carbone, Nicholas P.; Laakso, Markku; Agudelo, Leandro Z.; Pajukanta, Päivi; Hirshman, Michael F.; Middelbeek, Roeland; Grove, Kevin L.; Goodyear, Laurie J.; Kellis, M

doi:10.1016/j.cmet.2022.09.004

Cited by 45 publications

(39 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, other two recently published skeletal muscle single-cell datasets further corroborated our previous findings ( Fig. S6C, D ) (McKellar et al, 2021; Yang et al, 2022). Of note, the dataset of Yang and colleagues used forelimb triceps brachii skeletal muscle, which supports our findings exploring the dataset of Oprescu et al using hindlimb tibialis anterior muscle (Oprescu et al, 2020b; Yang et al, 2022).…”

Section: Resultssupporting

confidence: 91%

“…We next aimed to validate our previous single-cell transcriptomics findings using three public scRNAseq datasets (McKellar et al, 2021; Yang et al, 2022; Zhang et al, 2022). Using the dataset of Zhang and colleagues, we first observed that Lpar1, Lpar4, Enpp2 and Plpp3 were expressed by muscle FAPs, whereas tenocytes also expressed Lpar1 and Plpp3 ( Fig.…”

Section: Resultsmentioning

confidence: 98%

“…S6C, D ) (McKellar et al, 2021; Yang et al, 2022). Of note, the dataset of Yang and colleagues used forelimb triceps brachii skeletal muscle, which supports our findings exploring the dataset of Oprescu et al using hindlimb tibialis anterior muscle (Oprescu et al, 2020b; Yang et al, 2022). Furthermore, Yang and colleagues’ scRNAseq dataset from subcutaneous white adipose tissue also supports the notion of progenitor adipose stromal cells (ASCs), as cells highly expressing Lpar1, Lpar4, Enpp2 and Plpp3 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Single-Cell Transcriptome Dynamics of the Autotaxin-Lysophosphatidic Acid Axis During Muscle Regeneration Reveal Proliferative Effects in Mesenchymal Fibro-Adipogenic Progenitors

Contreras

2022

Preprint

View full text Add to dashboard Cite

Lysophosphatidic acid (LPA) is a growth factor-like bioactive phospholipid. As such, it has recently become an attractive target during tissue inflammation, repair, and regeneration, demonstrating biomedical relevance. LPA and LPA receptor-mediated signalling pathways regulate embryonic development, wound healing, carcinogenesis, and fibrosis, inducing cell migration, proliferation, and differentiation. Extracellular LPA is produced by the secreted hydrolase ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2, Autotaxin/ATX) and hydrolyzed by different membrane-bound phospholipid phosphatases (PLPPs). This study uses bulk and single-cell RNA sequencing to explore the gene expression dynamics of LPA receptors (LPARs), ENPP2, and PLPPs in skeletal muscle cells in homeostatic conditions and regeneration. Here, I show that skeletal muscle differentially expresses LPAR-Enpp2/ATX-PLPP coding genes, being Lpar1 the highest expressed member among LPARs. Lpar1 was highly expressed by FAPs and tenocytes, whereas Enpp2/ATX was mainly by FAPs. Clustering stromal fibro-adipogenic progenitors (FAPs) identified different populations representing distinct cell states with robust LPAR and Enpp2/ATX transcriptome signatures in homeostasis or resting-like cell states, including Dpp4+ and Hsd11b1+ FAPs. Tissue injury induces strong and fast repression of LPA receptors and Enpp2/ATX, indicating activated and proliferative FAP cell states are partly defined by a strong downregulation of LPAR and Enpp2/ATX gene expression. Hence, our results highlight the presence of the ATX-LPAR-PLPP axis in different muscle cells and FAP lineage in homeostasis and injury, providing a robust entry point for profound research on the role of LPA signalling skeletal muscle and other organs and tissues.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Single-Cell Transcriptome Dynamics of the Autotaxin-Lysophosphatidic Acid Axis During Muscle Regeneration Reveal Proliferative Effects in Mesenchymal Fibro-Adipogenic Progenitors

Contreras

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Our analysis has revealed an important role of monocytes/macrophages as well as microglia in the SVZ in the inflammatory changes in aging and after exercise. It has been implicated recently that the mesenchymal cells in the muscle and adipose tissues are involved in the remodeling of extracellular matrix in response to exercise and high-fat diet(Yang et al, 2022). Our cell-cell communication network analysis has revealed that FAPs, the mesenchymal progenitor cells in skeletal muscle, are one of the most prominent cell types that mediate intercellular signaling via extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging

Liu

Buckley

Reyes

et al. 2022

Preprint

View full text Add to dashboard Cite

Exercise has the ability to rejuvenate stem cells and improve tissue homeostasis and regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. To gain better insight into the mechanisms by which exercise affects niche and stem cell function, we subjected young and old mice to aerobic exercise and generated a single cell transcriptomic atlas of muscle, neural and hematopoietic stem cells with their niche cells and progeny. Complementarily, we also performed whole transcriptome analysis of single myofibers from these animals. We identified common and unique pathways that are compromised across these tissues and cell types in aged animals. We found that exercise has a rejuvenating effect on subsets of stem cells, and a profound impact in the composition and transcriptomic landscape of both circulating and tissue resident immune cells. Exercise ameliorated the upregulation of a number of inflammatory pathways as well as restored aspects of cell-cell communication within these stem cell compartments. Our study provides a comprehensive view of the coordinated responses of multiple aged stem cells and niche cells to exercise at the transcriptomic level.

show abstract

“…This suggests that the cellular impacts of both regimens may be regulated by a common upstream pathway that can control divergent downstream pathways, including circadian rhythm, thermogenesis, and fibro-inflammation in various cell populations. Indeed, a recent study illustrated that exercise upregulates circadian rhythm gene expressions, such as Dbp, and reduces fibro-inflammatory phenotype of APCs (Yang et al, 2022). These data, in parallel with our results, collectively suggest that not only circadian-aligned cues ( e.g., TRF) but other physiological or nutritional cues, such as exercise and prolonged fasting periods, can enhance circadian rhythm regardless of their alignment with central or peripheral clock rhythmicity.…”

Section: Discussionmentioning

confidence: 99%

Circadian reprogramming of adipose progenitor cells regulates intermittent fasting-mediated adipose tissue remodeling and metabolic improvement

Patel¹,

Yeung²,

Pickel³

et al. 2022

Preprint

View full text Add to dashboard Cite

White adipose tissue (WAT) fibrosis is a hallmark of dysfunctional WAT that is directly linked to metabolic abnormalities. Recent studies have highlighted the role of dysfunctional adipose progenitor cells (APCs) in WAT fibrosis and impaired adaptive tissue plasticity, leading to systemic insulin resistance. However, therapeutic options for WAT fibrosis are limited. Intermittent fasting (IF) is an effective dietary regimen for weight control and metabolic improvement through various mechanisms, including healthy remodeling of WAT. However, whether IF is effective in improving age- associated WAT fibrosis and metabolic homeostasis is unknown. Here, we show that IF confers therapeutic benefits in aged and obese mice through reduction of WAT fibrosis. Single-cell analyses revealed that IF significantly reduces pro-fibrotic signatures within APCs along with upregulation of the circadian pathways, suggesting that the circadian clock of APCs mediates IF-induced WAT remodeling. Importantly, mice lacking core circadian gene exhibited increased fibrotic signatures in WAT and diminished beneficial response to IF, further supporting the importance of circadian rhythm in IF-mediated metabolic benefits. Lastly, insulin resistance in humans also presented with dysregulated circadian rhythm signatures in APC populations. Collectively, our findings highlight the novel role of the APC circadian rhythm in plasticity of WAT and metabolic response to IF.

show abstract

Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells

Cited by 45 publications

References 98 publications

Single-Cell Transcriptome Dynamics of the Autotaxin-Lysophosphatidic Acid Axis During Muscle Regeneration Reveal Proliferative Effects in Mesenchymal Fibro-Adipogenic Progenitors

Single-Cell Transcriptome Dynamics of the Autotaxin-Lysophosphatidic Acid Axis During Muscle Regeneration Reveal Proliferative Effects in Mesenchymal Fibro-Adipogenic Progenitors

Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging

Circadian reprogramming of adipose progenitor cells regulates intermittent fasting-mediated adipose tissue remodeling and metabolic improvement

Contact Info

Product

Resources

About