https://ir.ymlib.yonsei.ac.kr/handle/22282913/168910 2026-05-13T13:14:08Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/211887 Title: Microenvironmental Reprogramming by 3D Anisotropic Cardiac Extracellular Matrix Induces Nuclear Remodeling and Epigenetic Maturation of Chemically Induced Cardiomyocytes Authors: Seo, Seung Ju; Lee, Mi Jeong; Kang, Hyun Wook; Byeon, Seonhee; Choi, Soo- Kyoung; Choi, Nakwon; Cho, Seung- Woo; Jin, Yoonhee Abstract: Extracellular matrix (ECM) of the heart exhibits highly organized anisotropy, which is essential for directing cellular alignment, force transmission, and tissue function. However, mechanistic pathways linking ECM alignment to nuclear and epigenetic remodeling remain poorly defined, especially in the context of direct cardiac reprogramming. Here, a 3D anisotropically aligned decellularized heart ECM (HEM) is engineered to investigate how structural and biochemical cues modulate maturation of chemically induced cardiomyocyte-like cells (CiCMs). The alignment of HEM enhances cytoskeletal organization and perinuclear actin assembly, leading to nuclear elongation and intermembrane redistribution of emerin from the inner to the outer nuclear membrane. These changes are accompanied by upregulation of SUN1/2, key components of the LINC complex, and by a transient increase in nuclear YAP/TAZ localization. Chromatin condensation is reduced under aligned conditions, with corresponding increases in H3K4me3 and decreases in H3K9me3, indicative of a more transcriptionally permissive chromatin state. Functionally, CiCMs in aligned HEM exhibit improved sarcomere structure and t-tubule development, enhanced responsiveness to beta-adrenergic and muscarinic stimulation, and increased contractile force under electrical pacing. These findings reveal a mechanotransductive cascade linking cardiac ECM alignment to nuclear and chromatin remodeling, ultimately promoting functional maturation of reprogrammed cardiomyocytes in a biomimetic 3D microenvironment. 2026-04-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/211886 Title: Scutellarein attenuates cancer cachexia-induced muscle atrophy via targeted inhibition of the JAK/STAT pathway Authors: Ahn, Heeju; Kim, Heeju; Yoon, Yeyoung; Jeong, Minju; Lee, Sieun; Chen, Peng; Wang, Keke; Park, Sujung; Kim, Jae Hwan; Ahn, Jiyun; Wang, Qiantao; Jin, Yoonhee; Jang, Young Jin; Byun, Sanguine Abstract: Introduction: Cancer cachexia is a multifaceted metabolic syndrome characterized by severe loss of skeletal muscle and adipose tissue, diminishing both quality of life and survival in cancer patients. Despite its prevalence, effective treatments for cancer cachexia remain limited. The JAK/STAT signaling pathway has been identified as a key driver of muscle atrophy in cachexia. Objectives: This study aimed to investigate the therapeutic potential of scutellarein, a natural compound, as a JAK kinase inhibitor to prevent and mitigate cancer cachexia-induced muscle atrophy. Methods: In vitro experiments were conducted using the mouse myoblast cell line C2C12 and human induced pluripotent stem cell (hiPSC)-derived skeletal muscle cells. Myotube atrophy was induced using IFN-c/TNF-a and cancer cell-conditioned media. Two independent mouse models of cancer cachexia were utilized for in vivo analysis. Muscle tissues were examined through transcriptomic and molecular analyses, including RNA sequencing, PCR, and immunoblotting. Structure-activity relationship studies and molecular docking analyses were performed to investigate the binding interaction of scutellarein with JAK kinases. Results: Through a chemical library screen, we identified scutellarein as a potent JAK kinase inhibitor. Scutellarein effectively mitigated myotube atrophy by inhibiting protein degradation and promoting protein synthesis in C2C12 and hiPSC-derived muscle cells. In two distinct mouse models of cancer cachexia, scutellarein treatment significantly reduced muscle wasting, improved muscle strength and function, and countered fat depletion. Transcriptomic and molecular analyses of muscle tissues further demonstrated that scutellarein inhibited activation of JAK/STAT pathways and restored suppression of myogenesis and mitochondrial biogenesis. Structure-activity relationship analyses further revealed critical hydroxyl group positions essential for JAK binding. Conclusion: Collectively, our findings suggest scutellarein as a promising candidate for the prevention and treatment of cancer cachexia, providing a novel therapeutic approach to address this critical unmet need in cancer care. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2026-04-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/212122 Title: Mechanically Spatio-Chimeric Fibrin Assembly Enables Vascular-Integrated Muscle Reconstruction for Volumetric Muscle Loss Repair Authors: Jung, Su Hyun; Kim, Minjun; Kim, Da-Yoon; Kim, Min Kyu; Lee, Sieun; Jin, Yoonhee; Kang, Joo H. Abstract: Volumetric muscle loss (VML), a severe injury involving irreversible loss of both muscle tissue and vasculature, poses a major barrier to the development of clinically viable muscle grafts. Functional restoration requires engineered constructs capable of reconstructing both contractile and vascular components that can functionally integrate with the host vasculature. Here, we introduce SPARC (spatio-chimeric, plasma-based, anisotropic, and shear-responsive construct), a mechanically bimodal fibrin hydrogel engineered via shear-guided assembly of plasma fibrin to recreate the structural and mechanical heterogeneity of native muscle. Controlled microfluidic shear generates aligned fibrillar bundles and a spatially graded bimodal stiffness architecture, establishing stiff, bundle-dense regions that favor myogenic differentiation and compliant regions that promote endothelial morphogenesis. When co-cultured with myoblasts and endothelial cells, the resulting anisotropic matrix directs spatially organized myogenic maturation and endothelial morphogenesis. In vivo evaluation in a murine VML model shows that vascularized muscle SPARC grafts restore muscle architecture and function, promoting neovascularization, myofiber regeneration, and enhanced motor recovery. Through its spatially mechano-programmed design, SPARC enables coordinated myogenic and endothelial organization within a single construct, establishing a scalable biofabrication strategy for functional repair of extensive muscle defects. 2026-04-01T00:00:00Z https://ir.ymlib.yonsei.ac.kr/handle/22282913/211522 Title: Retinoic acid signaling regulates astrocyte reactivity by modulating MAPK/ NF-κB pathways and mitochondrial integrity Authors: Yoo, Seo Hyun; Kim, Dongyun; Yeon, Gyu-Bum; Choi, Jaeyeon; Lee, Jaewook; Kim, Dong-Wook; Kim, Hyunggee; Kim, Dae-Sung Abstract: Astrocytes respond to inflammatory stimuli by adopting a reactive state characterized by morphological, molecular, and functional changes that affect tissue repair and disease progression. A key feature of this transformation is the metabolic shift that supports inflammatory signaling and cytokine production. Retinoic acid (RA) modulates immune responses in the peripheral system; however, its role in astrocyte reactivity remains poorly understood. In this study, we investigated alterations in RA metabolism using an in vitro model of reactive astrocytes derived from human pluripotent stem cells. Reactivity was induced by treatment with tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and complement component 1q (C1q), collectively referred to as TIC, and characterized using comprehensive morphological, molecular and functional analyses. We found that the induced reactive astrocytes exhibited a marked downregulation of key biosynthetic enzymes in RA metabolism, leading to a net decrease in intracellular RA levels. Exogenous RA supplementation attenuated TIC-induced expression of pro- and anti-inflammatory mediators, including IL-6, IL-8, nitric oxide, IL-10, and TGF beta. Mechanistically, RA suppressed these inflammatory responses by inhibiting NF-kappa B activation, likely through upstream attenuation of ERK and p38 MAPK pathways via upregulation of MAPK phosphatase 1 (MKP-1). In neuron and TIC-treated astrocyte co-cultures, RA treatment reduced the density of cleaved caspase 3-positive apoptotic-like neurons, an effect accompanied by decreased nitric oxide levels. These observations coincided with the restoration of mitochondrial integrity and mitophagy. Taken together, these findings identify RA metabolism as a key regulatory node in astrocyte reactivity and suggest a potential therapeutic role for RA in neuroinflammatory conditions. 2026-03-01T00:00:00Z