Heterochronic parabiosis for the study of the effects of aging on stem cells and their niche

ArticleinCell cycle (Georgetown, Tex.) 11(12):2260-7 · June 2012with52 Reads
DOI: 10.4161/cc.20437 · Source: PubMed
Abstract
Aging is unmistakable and undeniable in mammals. Interestingly, mice develop cataracts, muscle atrophy, osteoporosis, obesity, diabetes and cognitive deficits after just 2-3 postnatal years, while it takes seven or more decades for the same age-specific phenotypes to develop in humans. Thus, chronological age corresponds differently with biological age in metazoan species and although many theories exist, we do not understand what controls the rate of mammalian aging. One interesting idea is that species-specific rate of aging represents a ratio of tissue attrition to tissue regeneration. Furthermore, current findings suggest that the age-imposed biochemical changes in the niches of tissue stem cells inhibit performance of this regenerative pool, which leads to the decline of tissue maintenance and repair. If true, slowing down stem cell and niche aging, thereby promoting tissue regeneration, could slow down the process of tissue and organismal aging. In this regard, recent studies of heterochronic parabiosis provide important clues as to the mechanisms of stem cell aging and suggest novel strategies for enhancing tissue repair in the old. Here we review current literature on the relationship between the vigor of tissue stem cells and the process of aging, with an emphasis on the rejuvenation of old tissues by the extrinsic modifications of stem cell niches.
    • "The entirety of this process essentially reflects the hallmarks of aging for stem cell exhaustion and to some degree [8, 15] cellular senescence in humans. These hallmarks however are intended to capture the decline in regenerative potential of tissues that occurs with aging [1], considered to be in fact partially affected by cell extrinsic factors [16], and we will not further elaborate on these. Several other hallmarks of human aging will not be discussed in detail here, because they have limited relevance for natural aging in yeast, or they have not been robustly implicated in yeast aging. "
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    • "Expression profiles from 11 developmental stages were normalized, generating a GEO (GSE63860) showing the kinetics of each transcript over time (FiguresFigure 1Band Figure S3B), which were determined to be functionally homogeneous and easily aggregated in defined GO pathways (Figure S3B, Pathways). Furthermore, this in silico analysis of the transcriptome through categorization of expression trends (Figure 1Band Figure S3B, Pathways) and specific molecular signatures (Figures 1B–D), yielded known myogenic and related factors (Figure S3B, Genes) (Kuang et al., 2008; Abou-Khalil et al., 2009; Boldrin et al., 2012; Conboy and Rando, 2012). Strikingly, two transition events were revealed: (I) from embryonic to fetal myogenesis (Messina and Cossu, 2009), hypothesized to mark the early onset of satellite cell formation (Kassar-Duchossoy et al., 2005); and (II) the acquisition of quiescence in satellite cells around 3 weeks of age (Figures 1B,C; Lepper et al., 2009; White et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Skeletal muscle growth and regeneration require a population of muscle stem cells, the satellite cells, located in close contact to the myofiber. These cells are specified during fetal and early postnatal development in mice from a Pax3/7 population of embryonic progenitor cells. As little is known about the genetic control of their formation and maintenance, we performed a genome-wide chronological expression profile identifying the dynamic transcriptomic changes involved in establishment of muscle stem cells through life, and acquisition of muscle stem cell properties. We have identified multiple genes and pathways associated with satellite cell formation, including set of genes specifically induced (EphA1, EphA2, EfnA1, EphB1, Zbtb4, Zbtb20) or inhibited (EphA3, EphA4, EphA7, EfnA2, EfnA3, EfnA4, EfnA5, EphB2, EphB3, EphB4, EfnBs, Zfp354c, Zcchc5, Hmga2) in adult stem cells. Ephrin receptors and ephrins ligands have been implicated in cell migration and guidance in many tissues including skeletal muscle. Here we show that Ephrin receptors and ephrins ligands are also involved in regulating the adult myogenic program. Strikingly, impairment of EPHB1 function in satellite cells leads to increased differentiation at the expense of self-renewal in isolated myofiber cultures. In addition, we identified new transcription factors, including several zinc finger proteins. ZFP354C and ZCCHC5 decreased self-renewal capacity when overexpressed, whereas ZBTB4 increased it, and ZBTB20 induced myogenic progression. The architectural and transcriptional regulator HMGA2 was involved in satellite cell activation. Together, our study shows that transcriptome profiling coupled with myofiber culture analysis, provides an efficient system to identify and validate candidate genes implicated in establishment/maintenance of muscle stem cells. Furthermore, tour de force transcriptomic profiling provides a wealth of data to inform for future stem cell-based muscle therapies.
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    • "In recent years MSCs have generated a great deal of excitement as an attractive alternative to embryonic stem cells in cell-based regenerative medicine. In contrast to cells of embryonic origin, the clinical application of MSCs is restricted by their finite self-renewal capacity, in which they resemble the other somatic cells and exhibit both replicative aging (changes based on their replicative history) as well as chronological aging (age-related changes that occur in nondividing cells) [2]. Since senescence of MSCs causes disruption of tissue and organ maintenance, which is an obstacle to stem cell-based therapies for diseases, maintenance of natural MSC characteristics is very important. "
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