High-Throughput Screens for Embryonic Stem Cells: Stress-Forced Potency-Stemness Loss Enables Toxicological Assays

Li, Quanwen; Yu, Yang; Louden, Erica; Puscheck, Elizabeth E.; Rappolee, Daniel A.

doi:10.1007/7653_2016_66

Cited by 11 publications

(15 citation statements)

References 39 publications

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“…For example, introducing potency and/or first lineage differentiation reporters into ESCs and TSCs will provide a rapid way to screen for drugs, diet supplements, cosmetics, maternal stress hormones, and inflammatory and environmental stimuli [41,42,96] that may be potential pregnancy toxicants, since decreased ESC and TSC proliferation and forced-differentiation due to stress appear to apply for multiple types of stress tested. The cell types used for building HTSs should be extended to a variety of human racial and sex subtypes.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

“…Stress preferentially differentiates mTSCs toward the trophoblast giant cell (TGC) lineage [3]. We have studied stress such as hyperosmolarity for mTSCs, mESCs and embryos [36][37][38][39][40][41][42][43] and hypoxia below 2% for mTSCs [44]. Both types of stress induce heart and neural crest derivatives expressed 1 (HAND1) transcription factor and HAND1-dependent PL1 expression [37,44], thus inducing TGC differentiation in vitro despite the presence of FGF4 that should suppress PL1 [45].…”

Section: Understanding the High Rate Of Prenatal Embryo Loss From Thementioning

confidence: 99%

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Blastocyst-Derived Stem Cell Populations under Stress: Impact of Nutrition and Metabolism on Stem Cell Potency Loss and Miscarriage

Bolnick

Shamir

et al. 2017

Stem Cell Rev and Rep

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Data from in vitro and in vivo models suggest that malnutrition and stress trigger adaptive responses, leading to small for gestational age (SGA) blastocysts with fewer cell numbers. These stress responses are initially adaptive, but become maladaptive with increasing stress exposures. The common stress responses of the blastocyst-derived stem cells, pluripotent embryonic and multipotent placental trophoblast stem cells (ESCs and TSCs), are decreased growth and potency, and increased, imbalanced and irreversible differentiation. SGA embryos may fail to produce sufficient antiluteolytic placental hormone to maintain corpus luteum progesterone secretion that provides nutrition at the implantation site. Myriad stress inputs for the stem cells in the embryo can occur in vitro during in vitro fertilization/assisted reproductive technology (IVF/ART) or in vivo. Paradoxically, stresses that diminish stem cell growth lead to a higher level of differentiation simultaneously which further decreases ESC or TSC numbers in an attempt to functionally compensate for fewer cells. In addition, prolonged or strong stress can cause irreversible differentiation. Resultant stem cell depletion is proposed as a cause of miscarriage via a "quiet" death of an ostensibly adaptive response of stem cells instead of a reactive, violent loss of stem cells or their differentiated progenies.

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Section: Summary and Future Directionsmentioning

confidence: 99%

Section: Understanding the High Rate Of Prenatal Embryo Loss From Thementioning

confidence: 99%

Blastocyst-Derived Stem Cell Populations under Stress: Impact of Nutrition and Metabolism on Stem Cell Potency Loss and Miscarriage

Bolnick

Shamir

et al. 2017

Stem Cell Rev and Rep

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“…AMPK agonists like BR-DIM and metformin also lead to decreased growth and potency in Rex1 potency reporter-RFP reporter mESCs at higher doses [2] similar to decreased growth and Oct4 in blastocysts, and Rex1 and Cdx2 potency factors decrease in two-cell embryos [3,41]. Although AMPK is known to regulate polarity [47,48], AMPK agonists' biological effects at the blastocyst stage ( Fig.…”

Section: Discussionmentioning

confidence: 86%

“…AMPK inhibitors compound C and AraA block stress-forced potency loss in ESCs, TSC blastocysts, and two-cell embryos suggesting that AMPK mediates potency loss. Recently, it was shown that not only stress but also other non-stressful activators of AMPK such as Rx (aspirin, metformin) and diet supplements (BR-DIM but also resveratrol) cause potency loss in two-cell embryos and high throughput screen (HTS) ESC [2,3]. It was also shown that AMPK agonist Rx and diet supplement (DS) retard and arrest cell growth soon after initiation with cultured two-cell embryos and 2-3 days before the blastocyst stage.…”

Section: Introductionmentioning

confidence: 99%

Two-cell embryos are more sensitive than blastocysts to AMPK-dependent suppression of anabolism and stemness by commonly used fertility drugs, a diet supplement, and stress

Bolnick

Abdulhasan

Kilburn

et al. 2017

J Assist Reprod Genet

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“…The actual subpopulations of cells may not reflect the increase of markers which are assayed biochemically. ESCs also favor first lineage initially during 7 days culture of hyperosmotic stressed embryoid bodies and monolayers (Slater et al, ; Li et al, , ). Therefore, the descent down Waddington's channels is slowed by the indecision of stress, and whirlpools indicate a reversible, pseudo‐differentiated state.…”

Section: Redrawing Waddington's Epigenetic Channels With a Hypoxic Stmentioning

confidence: 99%

Hypoxic Stress Forces Adaptive and Maladaptive Placental Stress Responses in Early Pregnancy

Abdulhasan

Awonuga

et al. 2017

Birth Defects Research

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This review focuses on hypoxic stress and its effects on the placental lineage and the earliest differentiation events in mouse and human placental trophoblast stem cells (TSCs). Although the placenta is a decidual organ at the end of pregnancy, its earliest rapid growth and function at the start of pregnancy precedes and supports growth and function of the embryo. Earliest function requires that TSCs differentiate, however, "hypoxia" supports rapid growth, but not differentiation of TSCs. Most of the literature on earliest placental "hypoxia" studies used 2% oxygen which is normoxic for TSCs. Hypoxic stress happens when oxygen level drops below 2%. It decreases anabolism, proliferation, potency/stemness and increases differentiation, despite culture conditions that would sustain proliferation and potency. Thus, to study the pathogenesis due to TSC dysfunction, it is important to study hypoxic stress below 2%. Many studies have been performed using 0.5 to 1% oxygen in cultured mouse TSCs. From all these studies, a small number has examined human trophoblast lines and primary first trimester placental hypoxic stress responses in culture. Some other stress stimuli, aside from hypoxic stress, are used to elucidate common and unique aspects of hypoxic stress. The key outcomes produced by hypoxic stress are mitochondrial, anabolic, and proliferation arrest, and this is coupled with stemness loss and differentiation. Hypoxic stress can lead to depletion of stem cells and miscarriage, or can lead to later dysfunctions in placentation and fetal development. Birth Defects Research 109:1330-1344, 2017. © 2017 Wiley Periodicals, Inc.

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High-Throughput Screens for Embryonic Stem Cells: Stress-Forced Potency-Stemness Loss Enables Toxicological Assays

Cited by 11 publications

References 39 publications

Blastocyst-Derived Stem Cell Populations under Stress: Impact of Nutrition and Metabolism on Stem Cell Potency Loss and Miscarriage

Blastocyst-Derived Stem Cell Populations under Stress: Impact of Nutrition and Metabolism on Stem Cell Potency Loss and Miscarriage

Two-cell embryos are more sensitive than blastocysts to AMPK-dependent suppression of anabolism and stemness by commonly used fertility drugs, a diet supplement, and stress

Hypoxic Stress Forces Adaptive and Maladaptive Placental Stress Responses in Early Pregnancy

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