Dataset Information

Engineered Heterochronic Parabiosis in 3D Microphysiological System for Identification of Muscle Rejuvenating Factors.

ABSTRACT: Exposure of aged mice to a young systemic milieu revealed remarkable rejuvenation effects on aged tissues, including skeletal muscle. Although some candidate factors have been identified, the exact identity and the underlying mechanisms of putative rejuvenating factors remain elusive, mainly due to the complexity of in vivo parabiosis. Here, we present an in vitro muscle parabiosis system that integrates young- and old-muscle stem cell vascular niche on a three-dimensional microfluidic platform designed to recapitulate key features of native muscle stem cell microenvironment. This innovative system enables mechanistic studies of cellular dynamics and molecular interactions within the muscle stem cell niche, especially in response to conditional extrinsic stimuli of local and systemic factors. We demonstrate that vascular endothelial growth factor (VEGF) signaling from endothelial cells and myotubes synergistically contribute to the rejuvenation of the aged muscle stem cell function. Moreover, with the adjustable on-chip system, we can mimic both blood transfusion and parabiosis and detect the time-varying effects of anti-geronic and pro-geronic factors in a single organ or multi-organ systems. Our unique approach presents a complementary in vitro model to supplement in vivo parabiosis for identifying potential anti-geronic factors responsible for revitalizing aging organs.

SUBMITTER: Lee Y

PROVIDER: S-EPMC10697693 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Engineered Heterochronic Parabiosis in 3D Microphysiological System for Identification of Muscle Rejuvenating Factors.

Lee Yunki Y Choi Jeongmoon J JJ Ahn Song Ih SI Lee Nan Hee NH Han Woojin M WM Mohiuddin Mahir M Shin Eun Jung EJ Wood Levi L Park Ki Dong KD Kim YongTae Y Jang Young C YC

Advanced functional materials 20200826 46

Exposure of aged mice to a young systemic milieu revealed remarkable rejuvenation effects on aged tissues, including skeletal muscle. Although some candidate factors have been identified, the exact identity and the underlying mechanisms of putative rejuvenating factors remain elusive, mainly due to the complexity of <i>in vivo</i> parabiosis. Here, we present an <i>in vitro</i> muscle parabiosis system that integrates young- and old-muscle stem cell vascular niche on a three-dimensional microflu ...[more]

PMID: 38053980

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Project description:Statins are used to lower cholesterol and prevent cardiovascular disease. Musculoskeletal side effects known as statin associated musculoskeletal symptoms (SAMS), are reported in up to 10% of statin users, necessitating statin therapy interruption and increasing cardiovascular disease risk. We tested the hypothesis that, when exposed to statins ex vivo, engineered human skeletal myobundles derived from individuals with (n = 10) or without (n = 14) SAMS and elevated creatine-kinase levels exhibit statin-dependent muscle defects. Myoblasts were derived from muscle biopsies of individuals (median age range of 62-64) with hyperlipidemia with (n = 10) or without (n = 14) SAMS. Myobundles formed from myoblasts were cultured with growth media for 4 days, low amino acid differentiation media for 4 days, then dosed with 0 and 5μM of statins for 5 days. Tetanus forces were subsequently measured. To model the change of tetanus forces among clinical covariates, a mixed effect model with fixed effects being donor type, statin concentration, statin type and their two way interactions (donor type*statin concentration and donor type* statin type) and the random effect being subject ID was applied. The results indicate that statin exposure significantly contributed to decrease in force (P<0.001) and the variability in data (R2C [R square conditional] = 0.62). We found no significant differences in force between myobundles from patients with/without SAMS, many of whom had chronic diseases. Immunofluorescence quantification revealed a positive correlation between the number of straited muscle fibers and tetanus force (R2 = 0.81,P = 0.015) and negative correlation between number of fragmented muscle fibers and tetanus force (R2 = 0.482,P = 0.051) with no differences between donors with or without SAMS. There is also a correlation between statin exposure and presence of striated fibers (R2 = 0.833, P = 0.047). In patient-derived myobundles, statin exposure results in myotoxicity disrupting SAA organization and reducing force. We were unable to identify differences in ex vivo statin myotoxicity in this system. The results suggest that it is unlikely that there is inherent susceptibility to or persistent effects of statin myopathy using patient-derived myobundles.

Dataset Information

Engineered Heterochronic Parabiosis in 3D Microphysiological System for Identification of Muscle Rejuvenating Factors.

Publications

Engineered Heterochronic Parabiosis in 3D Microphysiological System for Identification of Muscle Rejuvenating Factors.

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