The mechanisms of response to hypoxia in embryonic stem cells

MUSILOVÁ, Julie, Jan KUČERA, Martina LÁNOVÁ, Kateřina ŠTEFKOVÁ, Lukáš KUBALA and Jiří PACHERNÍK. The mechanisms of response to hypoxia in embryonic stem cells (The mechanism of response to hypoxia in embryonic stem cells). In Stem Cells and Cell therapy: From research to modern clinical application. 2013.

Basic information

Original name

The mechanisms of response to hypoxia in embryonic stem cells

Name in Czech

Mechanismus odpovědi na hypoxii u embryonálních kmenových buněk

Authors

MUSILOVÁ, Julie (203 Czech Republic, belonging to the institution), Jan KUČERA (203 Czech Republic, belonging to the institution), Martina LÁNOVÁ (203 Czech Republic, belonging to the institution), Kateřina ŠTEFKOVÁ (203 Czech Republic, belonging to the institution), Lukáš KUBALA (203 Czech Republic, belonging to the institution) and Jiří PACHERNÍK (203 Czech Republic, guarantor, belonging to the institution)

Edition

Stem Cells and Cell therapy: From research to modern clinical application, 2013

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Other information

Language

English

Type of outcome

Prezentace na konferencích

Field of Study

30105 Physiology

Country of publisher

Czech Republic

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

RIV identification code

RIV/00216224:14310/13:00070750

Organization unit

Faculty of Science

Keywords (in Czech)

hypoxie kmenové buňky HIF

Keywords in English

hypoxia stem cells HIF

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Abstract

V originále

Oxygen is a crucial element for life of most organisms. Key regulator of oxygen sensing and responding intracellular machinery is heterodimeric transcription factor HIF1 (hypoxia inducible factor 1). Presence of oxygen leads to rapid ubiquitination and proteozomal degradation of cytoplasmic subunit HIF1alpha. This process is abolished in hypoxia, leading to accumulation of alpha subunit and dimerization with HIF1beta (also called ARNT). Upon binding of HIF1 heterodimer to hypoxia responsive elements, transcription of many specific genes involved in oxygen homeostasis is induced (Wang et al., 1995). Moreover hypoxia increases a production of intracellular reactive oxygen species (ROS) (Chandel et al., 2002). ROS can modulate cell signaling through transcription and also through posttranslational modifications of intracellular signaling pathways (Finkel, 2011). Additionally, further mechanisms of low oxygen sensing excluding the involvement of HIF and ROS were reported (Wouters and Koritzinsky, 2008). Thus, so called hypoxia signaling could be promoted via different HIF and ROS dependent and independent manners. Since hypoxia is known to regulate stem cell fate both in vivo and in vitro, the main aim of our study is to clarify the role of HIF and ROS in hypoxic response of embryonic stem cell. We used wild-type and HIF1alpha deficient (-/-) mouse embryonic stem cell (mES) to analyze signaling pathways responsible for stemness maintenance. We compared effects of hypoxia (1% O2) and pharmacologically induced stabilization of HIF in normoxic conditions on mES signaling. To clarify effects of ROS, various redox modulators were involved in our study. Posttranslational modifications of JAK/STAT3, MEK/ERK, PI3K/Akt, p38 and Notch signaling cascades were analyzed, as well as effects on proliferation, differentiation and apoptosis these mES cells. Our data show HIF1alpha and ROS-dependent down regulation of MEK/ERK signaling under hypoxic conditions. On the other hand, either hypoxia or ROS scavengers do not affect activation of JAK/STAT3 signaling. Activities of PI3K/Akt and p38 signaling pathways were downregulated independently on HIF1alpha or ROS. Interestingly, the pharmacological inhibition of prolylhydroxylases, which leads to increase of HIF1 stability in normoxia, does not affect any analyzed signaling pathways. In conclusion, our results clearly document the complexity of cellular responses to hypoxic conditions, where the important part of such responses is HIF1alpha independent.