Disease exacerbation in MYOrganoids derived from Duchenne Muscular Dystrophy iPSC reveals limitations of microdystrophin therapeutic efficacy DOI Creative Commons
Sonia Albini, Laura Palmieri,

Louna Pili

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Abstract Current gene therapy approaches for Duchenne muscular dystrophy (DMD) using AAV-mediated delivery of microdystrophin (µDys) have shown limited efficacy in patients, contrasting with the favorable outcomes observed animal models. This discrepancy is partly due to lack models that replicate key pathogenic features associated severity human disease, such as fibrosis and muscle dysfunction. To tackle translational gap, we develop a disease model recapitulates these critical hallmarks DMD more predictive therapeutic investigation. Using engineering approach, generate MYOrganoids from iPSC-derived cells co-cultured fibroblasts enable functional maturation force analysis upon contractions. Incorporation within allows phenotypic exacerbation by unraveling fibrotic signature fatiguability through cell-contact-dependent communication. Although µDys transfer partially restores resistance, it fails fully restore membrane stability reduce profibrotic signaling. These findings highlight persistence activity post-gene our system, an unparalleled aspect existing models, provide opportunity explore underlying mechanisms dysregulated cellular communication identify anti-fibrotic strategies empowering efficacy.

Language: Английский

Adipose tissue at single-cell resolution DOI Creative Commons
Babukrishna Maniyadath, Qianbin Zhang, Rana K. Gupta

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(3), P. 386 - 413

Published: March 1, 2023

Language: Английский

Citations

84
Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells DOI Creative Commons
Jiekun Yang, Maria Vamvini, Pasquale Nigro

et al.

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(10), P. 1578 - 1593.e6

Published: Oct. 1, 2022

Exercise training is critical for the prevention and treatment of obesity, but its underlying mechanisms remain incompletely understood given challenge profiling heterogeneous effects across multiple tissues cell types. Here, we address this opposing exercise high-fat diet (HFD)-induced obesity at single-cell resolution in subcutaneous visceral white adipose tissue skeletal muscle mice with interventions. We identify a prominent role mesenchymal stem cells (MSCs) exercise-induced adaptation. Among pathways regulated by HFD MSCs three tissues, extracellular matrix remodeling circadian rhythm are most prominent. Inferred cell-cell interactions implicate within- multi-tissue crosstalk centered around MSCs. Overall, our work reveals intricacies diversity molecular responses to uncovers previously underappreciated tissue-specific beneficial exercise.

Language: Английский

Citations

71
Adipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury DOI Creative Commons

Quentin Sastourné-Arrey,

Maxime Mathieu,

Xavier Contreras

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 5, 2023

Abstract Fibro-adipogenic progenitors (FAPs) play a crucial role in skeletal muscle regeneration, as they generate favorable niche that allows satellite cells to perform efficient regeneration. After injury, FAP content increases rapidly within the injured muscle, origin of which has been attributed their proliferation itself. However, recent single-cell RNAseq approaches have revealed phenotype and functional heterogeneity FAPs, raising question how this differentiation regenerative subtypes occurs. Here we report FAP-like residing subcutaneous adipose tissue (ScAT), stromal (ASCs), are released from ScAT response injury. Additionally, find ASCs infiltrate damaged via platelet-dependent mechanism thus contribute heterogeneity. Moreover, show either blocking infiltration or removing source impair Collectively, our data reveal is an unsuspected physiological reservoir support underlining beneficial relationship between fat.

Language: Английский

Citations

47
Impaired skeletal muscle regeneration in diabetes: From cellular and molecular mechanisms to novel treatments DOI Creative Commons
Ever Espino‐Gonzalez, Emilie Dalbram, Rémi Mounier

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(6), P. 1204 - 1236

Published: March 14, 2024

Diabetes represents a major public health concern with considerable impact on human life and healthcare expenditures. It is now well established that diabetes characterized by severe skeletal muscle pathology limits functional capacity quality of life. Increasing evidence indicates also one the most prevalent disorders impaired regeneration, yet underlying mechanisms therapeutic treatments remain poorly established. In this review, we describe cellular molecular alterations currently known to occur during regeneration in people animal models diabetes, including its associated comorbidities, e.g., obesity, hyperinsulinemia, insulin resistance. We role myogenic non-myogenic cell types conditions or without diabetes. Therapies for gaps our knowledge are discussed, while proposing future directions field.

Language: Английский

Citations

24
Histone deacetylase inhibition with givinostat: a multi-targeted mode of action with the potential to halt the pathological cascade of Duchenne muscular dystrophy DOI Creative Commons
Annemieke Aartsma‐Rus

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 6, 2025

Muscle repair and regeneration are complex processes. In Duchenne muscular dystrophy (DMD), these processes disrupted by the loss of functional dystrophin, a key part transmembrane dystrophin-associated glycoprotein that stabilizes myofibers, indirectly leading to progressive muscle wasting, subsequent ambulation, respiratory cardiac insufficiency, premature death. As DMD pathology, histone deacetylase (HDAC) activity is constitutively increased, epigenetic changes inhibition factors, chronic inflammation, fibrosis, adipogenesis. HDAC has consequently been investigated as therapeutic approach for dystrophies that, significantly, works independently from specific genetic mutations, making it potentially suitable all patients with DMD. This review discusses how addresses pathophysiology in multi-targeted mode action summarizes recent evidence on rationale givinostat, which now approved United States Food Drug Administration treatment aged 6 years older.

Language: Английский

Citations

2
Bidirectional roles of skeletal muscle fibro-adipogenic progenitors in homeostasis and disease DOI Creative Commons
Wentao Chen, Wenjing You, Teresa G. Valencak

et al.

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 80, P. 101682 - 101682

Published: July 7, 2022

Sarcopenia and myopathies cause progressive muscle weakness degeneration, which are closely associated with fat infiltration fibrosis in muscle. Recently, experimental research has shed light on fibro-adipogenic progenitors (FAPs), also known as muscle-resident mesenchymal multiple differentiation potential for adipogenesis, fibrosis, osteogenesis chondrogenesis. They considered key regulators of homeostasis integrity. play supportive roles development repair by orchestrating the regulatory interplay between stem cells (MuSCs) immune cells. Interestingly, FAPs contribute to intramuscular infiltration, other pathologies when functional integrity network is compromised. In this review, we summarize recent insights into maintenance skeletal homeostasis, discuss underlying mechanisms regulating behavior fate, highlighting their participating efficient infiltrated degeneration well during atrophy. We suggest that controlling predicting may become a promising strategy improve function prevent irreparable damage.

Language: Английский

Citations

58
Adipose-Derived Stem Cells: Angiogenetic Potential and Utility in Tissue Engineering DOI Open Access
Felor Biniazan, Alina Stoian, Siba Haykal

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(4), P. 2356 - 2356

Published: Feb. 16, 2024

Adipose tissue (AT) is a large and important energy storage organ as well an endocrine with critical role in many processes. Additionally, AT enormous easily accessible source of multipotent cell types used our day for all regeneration. The ability adipose-derived stem cells (ADSCs) to differentiate into other cells, such endothelial (ECs), vascular smooth muscle or cardiomyocytes, engineering order promote/stimulate the process angiogenesis. Being key future successful clinical applications, functional networks engineered are targeted by numerous vivo ex studies. article reviews angiogenic potential ADSCs explores their capacity field (TE).

Language: Английский

Citations

16
Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling DOI Creative Commons
Marcelo Flores‐Opazo, Daniel Kopinke, Françoise Helmbacher

et al.

Molecular Aspects of Medicine, Journal Year: 2024, Volume and Issue: 97, P. 101277 - 101277

Published: May 24, 2024

Excessive accumulation of intermuscular adipose tissue (IMAT) is a common pathological feature in various metabolic and health conditions can cause muscle atrophy, reduced function, inflammation, insulin resistance, cardiovascular issues, unhealthy aging. Although IMAT results from fat muscle, the mechanisms underlying its onset, development, cellular components, functions remain unclear. levels are influenced by several factors, such as changes environment, type origin, extent duration trauma, persistent activation fibro-adipogenic progenitors (FAPs). FAPs diverse transcriptionally heterogeneous population stromal cells essential for maintenance, neuromuscular stability, regeneration. However, cases chronic inflammation conditions, expand differentiate into adipocytes, resulting development abnormal ectopic IMAT. This review discusses role adipogenesis how they remodel It highlights evidence supporting FAP-derived adipocytes constituents IMAT, emphasizing their significance maintenance well involvement disorders, pathologies diseases. We also investigated intricate molecular pathways cell interactions governing FAP behavior, adipogenesis, diseases deconditioning. Finally, we hypothesize that impaired flexibility dysfunctional muscles impacts FAPs, leading to A deeper understanding biology regulating behavior fate new therapeutic strategies debilitating conditions.

Language: Английский

Citations

12
Skeletal muscle stem cells modulate niche function in Duchenne muscular dystrophy mouse through YY1-CCL5 axis DOI Creative Commons
Yang Li, Chuhan Li, Qiang Sun

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 3, 2025

Abstract Adult skeletal muscle stem cells (MuSCs) are indispensable for regeneration and tightly regulated by macrophages (MPs) fibro-adipogenic progenitors (FAPs) in their niche. Deregulated MuSC/MP/FAP interactions the ensuing inflammation fibrosis hallmarks of dystrophic muscle. Here we demonstrate intrinsic deletion transcription factor Yin Yang 1 (YY1) MuSCs exacerbates pathologies altering composition heterogeneity MPs FAPs. Further analysis reveals YY1 loss induces expression immune genes MuSCs, including C-C motif chemokine ligand 5 ( Ccl5 ). Augmented CCL5 secretion promotes MP recruitment via CCL5/C-C receptor (CCR5) crosstalk, which subsequently hinders FAP clearance through elevated Transforming growth factor-β1 (TGFβ1). Maraviroc-mediated pharmacological blockade CCL5/CCR5 axis effectively mitigates dystrophy improves performance. Lastly, represses binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study demonstrates critical role actively shaping niche provides novel insight into therapeutic intervention dystrophy.

Language: Английский

Citations

1
SPP1 macrophages across diseases: A call for reclassification? DOI Creative Commons
Alessio Reggio, Claudia Fuoco, Rebecca Deodati

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(5)

Published: March 6, 2025

SPP1+ macrophages, characterized by elevated expression of the osteopontin gene (secreted phosphoprotein 1, SPP1), have emerged as key players in various pathological contexts, including aging, chronic inflammatory diseases, and cancer. While frequently classified a subclass tumor-associated macrophages oncological settings, their presence noncancer conditions, such aging-related disorders muscular suggests broader role beyond tumors. These share conserved traits, fibrosis promotion, extracellular matrix remodeling, immune modulation, often linked to poor clinical outcomes. This perspective explores multifaceted roles across diseases advocates for reclassification distinct macrophage subtype associated with or prolonged inflammation. Recognizing cross-disease relevance could reshape biology inform targeted therapeutic strategies.

Language: Английский

Citations

1