Editor's evaluation: In vivo transcriptomic profiling using cell encapsulation identifies effector pathways of systemic aging

Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here, we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence(definition), and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy. Editor's evaluation The manuscript includes in vivo studies where encapsulated myogenic progenitors are exposed to the systemic environment of young or aged mice. The authors provide a very important comparison of a novel approach to the use of young or aged serum in vitro, which is considered the current gold standard. The studies reported also provide evidence that the in vivo capsule-based method may constitute an alternative and possibly improved approach to the study of impact of environment-related changes on function of skeletal muscle progenitors. https://doi.org/10.7554/eLife.57393.sa0 Decision letter eLife's review process Introduction Systemic cross-talk between tissues has emerged as an important determinant of organismal aging (Demontis et al., 2013). Supporting this notion, several features of tissue aging can be slowed or reversed by heterochronic parabiosis (Bert, 1864; Conboy et al., 2015). Restoration of a youthful systemic environment has been shown to improve the function of muscle, heart, liver, brain, and other tissues in aged mice (Baht et al., 2015; Conboy et al., 2005; Katsimpardi et al., 2014; Loffredo et al., 2013; Ruckh et al., 2012; Sinha et al., 2014; Smith et al., 2015; Villeda et al., 2011). Interestingly, the positive effects of young blood on aged tissues appear to be milder than the pronounced negative effects of aged blood on young tissues (Rebo et al., 2016). This observation suggests the presence of dominant pro-aging factors in the systemic circulation, which cross-talk with local tissue niches to induce the global decline in organ function associated with old age. Recent studies have aimed at identifying the circulating factors involved in systemic aging, and some of the experimental interpretations have led to considerable controversy in the field (Conese et al., 2017). It has long been known that a range of endocrine hormones are perturbed in later stages of life. Aging affects the somatotroph axis leading to decreased levels of growth hormone and insulin-like growth factor 1 (IGF-1) (Garcia et al., 2000). Levels of sex hormones such as testosterone and estrogen drop in aged individuals (Medicine, 2004). Old age is also associated with increased systemic inflammation that often goes along with a metabolic syndrome attributed to insulin resistance and an excessive flux of fatty acids (Dominguez and Barbagallo, 2016; Franceschi and Campisi, 2014). Next to these broad biological processes, several distinct pro- and anti-aging factors have been identified in the systemic environment. These include growth differentiation factor 15 (GDF15), eotaxin, β2-microglobulin, and transforming growth factor-β, which negatively affect brain or muscle tissue in aging (Lehallier et al., 2019; Smith et al., 2015; Tanaka et al., 2018; Villeda et al., 2011; Yousef et al., 2015). Factors activating Notch, growth differentiation factor 11 (GDF11), and tissue inhibitor of metalloproteinases 2 (TIMP-2), on the other hand, have been suggested to have rejuvenating effects (Castellano et al., 2017; Conboy et al., 2005; Conboy and Rando, 2002; Mahmoudi et al., 2019), although the role of GDF11 is still controversial (Egerman et al., 2015; Egerman and Glass, 2019; Harper et al., 2016; Schafer et al., 2016; Sinha et al., 2014). In addition, transcript levels of the prolongevity protein Klotho in circulating extracellular vesicles decrease with aging (Sahu et al., 2021). The modulation of age affected signaling pathways, represents a promising alternative to supplying or inhibiting systemic factors for rejuvenation. However, the study of pathways that are responsive to systemic changes is complicated by the heterogeneous composition of tissues, which contain a multitude of cell types that communicate through secreted short-range signals. Systemic factors do not always act in a direct manner on tissue-resident cell populations but can instead trigger paracrine propagation and modulation of signals through accessory cell types in the niche. In the intestinal crypt, paneth cells are known to transmit systemic signals induced by caloric restriction(definition) to intestinal stem cells (Yilmaz et al., 2012). Moreover, fibro-adipogenic progenitors, an age-affected support cell population for skeletal muscle stem cells, are highly susceptible to systemic cytokines (Biferali et al., 2019; Lukjanenko et al., 2019). Factors in the aging circulation also alter accessory cell signaling in the neurogenic niche, which contributes to neural stem cell dysfunction (Smith et al., 2018). These examples illustrate that profiling of aging pathways that are directly affected by systemic long-range signaling factors requires an approach that allows to subtract t