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

Abstract

Exposure of a young systemic milieu reveals remarkable rejuvenation effects on aged tissues, including skeletal muscle. Although some candidate factors have been reported, the exact underlying mechanisms of putative rejuvenating factors remain elusive, mainly due to the experimental challenges of using in vivo parabiosis. An in vitro parabiosis system is reported here that integrates young-and old-muscle stem cell vascular niche on a 3D microfluidic platform designed to recapitulate key features of native muscle stem cell microenvironment. This 3D micro-physiological 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. Using engineered parabiosis system, it is demonstrated that vascular endothelial growth factor signaling from endothelial cells and myotubes synergistically contributes to the rejuvenation of the aged muscle stem cell function. Moreover, with the adjustable on-chip system, both blood transfusion and parabiosis can be mimicked and the time-varying effects of antigeronic and progeronic factors can be monitored in a single organ or multiorgan systems. The microfluidic system can be utilized as a complementary in vitro microphysiological model to aid the complex in vivo parabiosis studies.

Microfluidics for Drug Development: From Synthesis to Evaluation

“…Multiorgan-on-a-Chip. In addition to the above-mentioned organs-on-chips, there are other kinds of organ-on-a-chip platforms, such as bone-on-a-chip, , skin-on-a-chip, , vessel-on-a-chip, , muscle-on-a-chip, − reproductive-organ-on-a-chip, etc. More attractively, the construction of multiorgan-on-a-chip platforms, i.e.…”

“…Concept of human-body-on-a-chip: diversified organ-on-a-chip systems recapitulating selected physiological characteristics of specific human organs, including the lung (adapted with permission from ref , copyright 2010 American Association for the Advancement of Science), heart (adapted with permission from ref , copyright 2018 the authors of ref under exclusive license to the American Association for the Advancement of Science), kidney (adapted with permission from ref , copyright 2013 Oxford University Press), muscle (adapted with permission from ref , copyright 2020 Wiley-VCH), brain (adapted with permission from ref , copyright 2020 Elsevier), liver (from ref , CC BY 4.0), gut (adapted from ref , published by the National Academy of Sciences), ovary and uterus (adapted with permission from ref , copyright 2020 IOP Publishing), etc. The realization of a human-body-on-a-chip platform relies on the systematic combination of different organ-on-a-chip models.…”

Recent Trends in Biofabrication Technologies for Studying Skeletal Muscle Tissue-Related Diseases

“…Moreover, they defined the factors that could assist satellite cell quiescence in vitro and applied it in the culture of the engineered muscle ( Quarta et al, 2016 ). Alternatively, Lee et al (2020) utilized a 3D microfluidic platform to establish vascular architecture of the satellite cell niche in vitro , where the intercirculation of niche factors between young and old satellite cells were demonstrated ( Lee et al, 2020 ). These models are potentially useful for modelling the satellite cell activation, quiescence, self-renewal and differentiation ( Ishii et al, 2018 ; Csapo et al, 2020 ) which all aid in skeletal muscle self-repair mechanism ( Figure 6 ).…”

“…Endogenous muscle self-repair is supported by interactions between muscle satellite cells and multiple types of muscle-resident cells, including macrophages, CD3 + T cells, endothelial cells, and fibro-adipogenic progenitors that collectively form a complex inflammatory milieu ( Fu et al, 2015 ; Quarta et al, 2017 ; Judson et al, 2020 ). However, current in vitro models of muscle self-repair partially recapitulate the microenvironment of the regenerating muscle, as satellite cells are co-cultured with either macrophages or endothelial cells ( Juhas et al, 2018 ; Lee et al, 2020 ). Therefore, the incorporation of multiple cell types is required for an in-depth understanding of the mechanism of satellite cell quiescence in regenerating muscles.…”

Transcriptional Profiling of Skeletal Muscle Stem Cells After In Vivo Engraftment into a Heterologous Niche Environment

“…The niche environment includes neighboring cell types such as fibro‐adipogenic progenitor cells (FAPs), immune cells, the myofibers upon which the MuSCs reside, and the extracellular matrix (ECM) that surrounds the MuSCs among others (Andrea J. de Micheli et al., 2020; Yin et al., 2013). Understanding how the niche regulates MuSC function is a current topic of great interest, and as such, has led to the generation of multiple in vitro niche models (Laternser et al., 2018; Lee et al., 2020; Maffioletti et al., 2018; Moyle et al., 2020; Quarta et al., 2016), sometimes employing bioengineering methods (Laternser et al., 2018; Lee et al., 2020; Moyle et al., 2020).…”