Neoblasts are adult stem cells (ASCs) in planarians that sustain cell replacement during homeostasis and regeneration of any missing tissue. While numerous studies have examined genes underlying neoblast pluripotency, molecular pathways driving postmitotic fates remain poorly defined. In this study, we used transcriptional profiling of irradiation-sensitive and irradiation-insensitive cell populations and RNA interference (RNAi) functional screening to uncover markers and regulators of postmitotic progeny. We identified 32 new markers distinguishing two main epithelial progenitor populations and a planarian homolog to the MEX3 RNA-binding protein (Smed-mex3-1) as a key regulator of lineage progression. mex3-1 was required for generating differentiated cells of multiple lineages, while restricting the size of the stem cell compartment. We also demonstrated the utility of using mex3-1(RNAi) animals to identify additional progenitor markers. These results identified mex3-1 as a cell fate regulator, broadly required for differentiation, and suggest that mex3-1 helps to mediate the balance between ASC self-renewal and commitment.DOI: http://dx.doi.org/10.7554/eLife.07025.001
Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.
Neoblasts are adult stem cells (ASCs) in planarians that sustain cell replacement during homeostasis and regeneration of any missing tissue. While numerous studies have examined genes underlying neoblast pluripotency, molecular pathways driving postmitotic fates remain poorly defined. In this study, we used transcriptional profiling of irradiation-sensitive and irradiationinsensitive cell populations and RNA interference (RNAi) functional screening to uncover markers and regulators of postmitotic progeny. We identified 32 new markers distinguishing two main epithelial progenitor populations and a planarian homolog to the MEX3 RNA-binding protein (Smed-mex3-1) as a key regulator of lineage progression. mex3-1 was required for generating differentiated cells of multiple lineages, while restricting the size of the stem cell compartment. We also demonstrated the utility of using mex3-1(RNAi) animals to identify additional progenitor markers. These results identified mex3-1 as a cell fate regulator, broadly required for differentiation, and suggest that mex3-1 helps to mediate the balance between ASC self-renewal and commitment.
2 Premature senescence in low birth weight rodents is associated with later life metabolic 3 disease, including the development of insulin resistance. Telomerase, a reverse 4 transcriptase enzyme with telomeric and non-telomeric functions, is present at high levels 5 during development to maintain and repair long telomere lengths and to protect cells from 6 oxidative stress-induced growth arrest. Adverse In utero environments are often associated 7 with increased reactive oxygen species (ROS), and ROS have been documented to 8 impair/alter telomerase function. We postulate that telomerase protects cells against 9 oxidative stress-induced damage, and its inhibition could lead to premature senescence. A 10 primary cell line of fetal guinea pig muscle cells was differentiated under high (20%) and 11 low (1-2%) oxygen concentrations and telomerase activity was pharmacologically inhibited 12 using a synthetic tea catechin. Following 48 hours, ROS detection was conducted with 13 MitoSOX, Mitotracker and 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate staining.14 Cells cultured at 20% O 2 and treated with a telomerase activity inhibitor displayed reduced 15 cell growth rates and increased levels of senescence markers, including p21 and p53.16 Telomeric DNA damage, measured by phosphorylated-γH2A.X staining at telomeres, was 17 significantly increased in cells cultured at all oxygen concentrations with telomerase 18 inhibition. Telomerase inhibition altered metabolic signaling (e.g. mTOR, p66Shc) and 19 increased mitochondrial ROS levels. Telomerase may protect cells during development from 20 adverse in utero environments that cause premature senescence. 2122 Key Words: DOHaD, intrauterine growth restriction, metabolism, telomerase, telomeric 23 DNA damage, senescence, reactive oxygen species 3 1 Introduction 2 A great number of human epidemiological and animal model studies have reported strong 3 associations between the birth phenotype, particularly birth weight, and risk for many 4 complex common adult diseases in later life, including hypertension, coronary artery 5 disease and diabetes [1, 2]. Adverse intrauterine environments due to maternal 6 malnutrition, hypertension, and placental insufficiency cause alterations in oxygen and 7 nutrient supply that results in intrauterine growth restriction (IUGR) where a fetus fails to 8 reach its genetic growth potential [3][4][5]. The redistribution of nutritional resources leads to 9 a decrease in muscularity and an increase in the percentage of body fat in these infants that 10 lasts throughout childhood and adult life [6, 7] in association with changes in insulin 11 sensitivity and other markers of metabolic syndrome [8, 9]. The effects of impaired growth 12 during in utero life are exacerbated by a rapid postnatal growth [10,11] and appear to 13 predispose offspring to an increased risk of disease in later life, or the concept of 14 developmental origins of health and disease (DOHaD) [12]. 15Although the molecular and cellular mechanisms underlying the association...
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