Emin Maltepe, MD, PhD

Associate Professor
Department of Pediatrics
+1 415 476-9313

Our laboratory is interested in the intersection of genetic, epigenetic and environmental factors during stem cell fate determination. Specifically, we study the role of mitochondrial oxygen sensing pathways and the Hypoxia-inducible Factor (HIF) family of transcriptional regulators during cell fate determination in the placenta. We previously demonstrated that oxygen tension is a developmental morphogen by genetically inactivating the transcription factor Hypoxia-inducible Factor-1. Embryos that could not mount a transcriptional response to hypoxia were unable to vascularize properly and exhibited defects in cardiac, hematopoietic and placental development. Trophoblast Stem (TS) cells are the extraembryonic equivalent of embryonic stem (ES) cells and give rise to all cell types that comprise the placenta. Utilizing TS cells we have been able to show that the proliferation of lineage-committed progenitors can be regulated by oxygen tension in a HIF-dependent fashion. Additionally, we have identified a novel oxygen-independent means of HIF activation that is also responsible for fundamental cell fate decisions. HIF-deficient TS cells adopt altered cell fates, differentiating into multinucleated syncytiotrophoblasts that line the maternal-fetal blood sinuses as opposed to trophoblast giant cells responsible for anchoring the placenta to the uterus and invading the maternal arterioles. This ability of HIF to regulate cell fate is dependent on an interaction between HIF and Histone Deacetylase (HDAC)-dependent epigenetic pathways. These results indicate that HIF plays a central role in integrating physiological, genetic and epigenetic pathways to regulate cell fate in the placenta. As the placenta is the primary maternal-fetal interface, an understanding of HIF’s role during TS cell fate determination will yield insights into normal placental development as well as placental pathologies such as preeclampsia (PE), intrauterine growth restriction (IUGR) and the fetal programming of adult disease (Barker Hypothesis).

Currently, we are focused primarily on defining the role of mitochondria during oxygen-dependent cell fate decisions. Specifically, we are examining changes in electron transport chain (ETC) components to help define the nature of the cellular oxygen sensor. Also, we are dissecting the interface between mitochondrial electron transport and downstream signaling pathways using a combination of biochemical, genetic and pharmacological approaches. We have determined that the formation of reactive oxygen species (ROS) by the mitochondrial ETC is responsible for regulating terminal differentiation events in the placenta in an oxygen-dependent manner. Utilizing antioxidants targeted specifically to mitochondria we are able to reverse the effects of hypoxic culture conditions in the placenta and hope to help devise clinical therapeutic strategies utilizing such agents to treat pregnancy complications such as PE and IUGR.

Additionally, we are very interested in mechanisms enabling cell fusion in the placenta. Syncytiotrophoblasts arise as a result of cell fusion that appears to be dependent on profound cytoskeletal rearrangements. Specifically, dramatic disruption of the cellular microtubule network accompanies cell fusion. Importantly, mitochondria are tightly associated with microtubules and the ability of mitochondrial ROS to affect cell fusion in the placenta appears to be due to the close physical association of these two cellular structures. We hope that defining the components of this localized signaling axis will help us develop novel therapeutic targets for the management of pregnancy complications.

Research Summary: 
The Regulation of Cell Fate by Oxygen and Mitochondria
Publications: 

The Gag Protein PEG10 Binds to RNA and Regulates Trophoblast Stem Cell Lineage Specification.

bioRxiv

Mona Abed,Erik Verschueren,Hanna Budayeva,Peter Liu,Donald Kirkpatrick,Rohit Reja,Sarah Kummerfeld,Joshua Webster,Sarah Gierke,Mike Reichelt,Keith Anderson,Robert Newman,Merone Roose-Girma,Zora Modrusan,Hazal Pektas,Emin Maltepe,Kim Newton,Vishva Dixit

Transcriptional signatures throughout development: the effects of mouse embryo manipulation in vitro.

Reproduction

Sky K Feuer,Xiaowei Liu,Annemarie Donjacour,Rhodel Simbulan,Emin Maltepe,Paolo Rinaudo

Effect of ICSI on gene expression and development of mouse preimplantation embryos.

Human Reproduction

G. Giritharan,M.W. Li,F. Di Sebastiano,F.J. Esteban,J.A. Horcajadas,K.C.K. Lloyd,A. Donjacour,E. Maltepe,P.F. Rinaudo