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: 

Outcomes of pulmonary vascular disease in infants conceived with non-IVF fertility treatment and assisted reproductive technologies at 1 year of age.

Pediatric pulmonology

Fineman DC, Baer RJ, Chambers CD, Rajagopal S, Maltepe E, Rinaudo PF, Fineman JR, Jelliffe-Pawlowski LL, Steurer MA

Pulmonary Endothelial Mechanical Sensing and Signaling, a Story of Focal Adhesions and Integrins in Ventilator Induced Lung Injury.

Frontiers in physiology

Kelly GT, Faraj R, Zhang Y, Maltepe E, Fineman JR, Black SM, Wang T

The Gag protein PEG10 binds to RNA and regulates trophoblast stem cell lineage specification.

PloS one

Abed M, Verschueren E, Budayeva H, Liu P, Kirkpatrick DS, Reja R, Kummerfeld SK, Webster JD, Gierke S, Reichelt M, Anderson KR, Newman RJ, Roose-Girma M, Modrusan Z, Pektas H, Maltepe E, Newton K, Dixit VM

BIOMECHANICAL FORCES AND OXIDATIVE STRESS: IMPLICATIONS FOR PULMONARY VASCULAR DISEASE.

Antioxidants & redox signaling

Zemskov E, Lu Q, Wojciech Ornatowski W, Klinger CN, Desai AA, Maltepe E, Yuan JX, Wang T, Fineman JR, Black S

Murine trophoblast-derived and pregnancy-associated exosome-enriched extracellular vesicle microRNAs: Implications for placenta driven effects on maternal physiology.

PloS one

Stefanski AL, Martinez N, Peterson LK, Callahan TJ, Treacy E, Luck M, Friend SF, Hermesch A, Maltepe E, Phang T, Dragone LL, Winn VD

Correction: Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic.

PLoS biology

Boehme J, Le Moan N, Kameny RJ, Loucks A, Johengen MJ, Lesneski AL, Gong W, Goudy BD, Davis T, Tanaka K, Davis A, He Y, Long-Boyle J, Ivaturi V, Gobburu JVS, Winger JA, Cary SP, Datar SA, Fineman JR, Krtolica A, Maltepe E

Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling.

American journal of respiratory cell and molecular biology

Johnson Kameny R, Datar SA, Boehme JB, Morris C, Zhu T, Goudy BD, Johnson EG, Galambos C, Raff GW, Sun X, Wang T, Chiacchia SR, Lu Q, Black SM, Maltepe E, Fineman JR

Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic.

PLoS biology

Boehme J, Le Moan N, Kameny RJ, Loucks A, Johengen MJ, Lesneski AL, Gong W, Davis T, Tanaka K, Davis A, He Y, Long-Boyle J, Ivaturi V, Gobburu JVS, Winger JA, Cary SP, Datar SA, Fineman JR, Krtolica A, Maltepe E

KLF2-mediated Disruption of PPAR? Signaling in Lymphatic Endothelial Cells Exposed to Chronically Increased Pulmonary Lymph Flow.

American journal of physiology. Heart and circulatory physiology

Morris CJ, Kameny RJ, Boehme J, Gong W, He Y, Zhu T, Maltepe E, Raff GW, Fineman JR, Datar SA

Sonic Hedgehog Agonist Protects Against Complex Neonatal Cerebellar Injury.

Cerebellum (London, England)

Nguyen V, Sabeur K, Maltepe E, Ameri K, Bayraktar O, Rowitch DH

Altered Carnitine Homeostasis in Children With Increased Pulmonary Blood Flow Due to Ventricular Septal Defects.

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Black SM, Field-Ridley A, Sharma S, Kumar S, Keller RL, Kameny R, Maltepe E, Datar SA, Fineman JR

Common and specific transcriptional signatures in mouse embryos and adult tissues induced by in vitro procedures.

Reproduction (Cambridge, England)

Feuer S, Liu X, Donjacour A, Simbulan R, Maltepe E, Rinaudo P

Pulmonary artery smooth muscle cell hyperproliferation and metabolic shift triggered by pulmonary overcirculation.

American journal of physiology. Heart and circulatory physiology

Boehme J, Sun X, Tormos KV, Gong W, Kellner M, Datar SA, Kameny RJ, Yuan JX, Raff GW, Fineman JR, Black SM, Maltepe E

Disrupted NOS signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow.

American journal of physiology. Heart and circulatory physiology

Datar SA, Gong W, He Y, Johengen M, Kameny RJ, Raff GW, Maltepe E, Oishi PE, Fineman JR

Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung.

PloS one

Rafikova O, Meadows ML, Kinchen JM, Mohney RP, Maltepe E, Desai AA, Yuan JX, Garcia JG, Fineman JR, Rafikov R, Black SM

Adult male mice conceived by in vitro fertilization exhibit increased glucocorticoid receptor expression in fat tissue.

Journal of developmental origins of health and disease

Simbulan RK, Liu X, Feuer SK, Maltepe E, Donjacour A, Rinaudo P

Placenta: the forgotten organ.

Annual review of cell and developmental biology

Maltepe E, Fisher SJ

HIGD1A-mediated dormancy and tumor survival.

Molecular & cellular oncology

Ameri K, Maltepe E

Embryonic stem cells derived from in vivo or in vitro-generated murine blastocysts display similar transcriptome and differentiation potential.

PloS one

Simbulan RK, Di Santo M, Liu X, Lin W, Donjacour A, Maltepe E, Shenoy A, Borini A, Rinaudo P

Spare hypoxia, spoil the child?

The Journal of clinical investigation

Boehme J, Maltepe E

HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth.

Cell reports

Ameri K, Jahangiri A, Rajah AM, Tormos KV, Nagarajan R, Pekmezci M, Nguyen V, Wheeler ML, Murphy MP, Sanders TA, Jeffrey SS, Yeghiazarians Y, Rinaudo PF, Costello JF, Aghi MK, Maltepe E

LIMK1 regulates human trophoblast invasion/differentiation and is down-regulated in preeclampsia.

The American journal of pathology

Zhou Y, Yuge A, Rajah AM, Unek G, Rinaudo PF, Maltepe E

Sexually dimorphic effect of in vitro fertilization (IVF) on adult mouse fat and liver metabolomes.

Endocrinology

Feuer SK, Donjacour A, Simbulan RK, Lin W, Liu X, Maltepe E, Rinaudo PF

Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis.

Cell

Yuen TJ, Silbereis JC, Griveau A, Chang SM, Daneman R, Fancy SPJ, Zahed H, Maltepe E, Rowitch DH

Use of a mouse in vitro fertilization model to understand the developmental origins of health and disease hypothesis.

Endocrinology

Feuer SK, Liu X, Donjacour A, Lin W, Simbulan RK, Giritharan G, Piane LD, Kolahi K, Ameri K, Maltepe E, Rinaudo PF

Placental syncytium forms a biophysical barrier against pathogen invasion.

PLoS pathogens

Zeldovich VB, Clausen CH, Bradford E, Fletcher DA, Maltepe E, Robbins JR, Bakardjiev AI

Hypoxia and trophoblast differentiation: a key role for PPAR?.

Stem cells and development

Tache V, Ciric A, Moretto-Zita M, Li Y, Peng J, Maltepe E, Milstone DS, Parast MM

Nuclear localization of the mitochondrial factor HIGD1A during metabolic stress.

PloS one

Ameri K, Rajah AM, Nguyen V, Sanders TA, Jahangiri A, Delay M, Donne M, Choi HJ, Tormos KV, Yeghiazarians Y, Jeffrey SS, Rinaudo PF, Rowitch DH, Aghi M, Maltepe E

The effect of hypoxia on facial shape variation and disease phenotypes in chicken embryos.

Disease models & mechanisms

Smith F, Hu D, Young NM, Lainoff AJ, Jamniczky HA, Maltepe E, Hallgrimsson B, Marcucio RS

ECM-dependent HIF induction directs trophoblast stem cell fate via LIMK1-mediated cytoskeletal rearrangement.

PloS one

Choi HJ, Sanders TA, Tormos KV, Ameri K, Tsai JD, Park AM, Gonzalez J, Rajah AM, Liu X, Quinonez DM, Rinaudo PF, Maltepe E

Effect of substrate stiffness on early mouse embryo development.

PloS one

Kolahi KS, Donjacour A, Liu X, Lin W, Simbulan RK, Bloise E, Maltepe E, Rinaudo P

Impaired placental nutrient transport in mice generated by in vitro fertilization.

Endocrinology

Bloise E, Lin W, Liu X, Simbulan R, Kolahi KS, Petraglia F, Maltepe E, Donjacour A, Rinaudo P

In vitro culture of mouse embryos reduces differential gene expression between inner cell mass and trophectoderm.

Reproductive sciences (Thousand Oaks, Calif.)

Giritharan G, Delle Piane L, Donjacour A, Esteban FJ, Horcajadas JA, Maltepe E, Rinaudo P

A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia.

Development (Cambridge, England)

Hunkapiller NM, Gasperowicz M, Kapidzic M, Plaks V, Maltepe E, Kitajewski J, Cross JC, Fisher SJ

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

Human reproduction (Oxford, England)

Giritharan G, Li MW, Di Sebastiano F, De Sebastiano F, Esteban FJ, Horcajadas JA, Lloyd KC, Donjacour A, Maltepe E, Rinaudo PF

Hypoxia-inducible factor (HIF) and HIF-stabilizing agents in neonatal care.

Seminars in fetal & neonatal medicine

Park AM, Sanders TA, Maltepe E

Effect of the method of conception and embryo transfer procedure on mid-gestation placenta and fetal development in an IVF mouse model.

Human reproduction (Oxford, England)

Delle Piane L, Lin W, Liu X, Donjacour A, Minasi P, Revelli A, Maltepe E, Rinaudo PF

The placenta: transcriptional, epigenetic, and physiological integration during development.

The Journal of clinical investigation

Maltepe E, Bakardjiev AI, Fisher SJ

Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation.

The Journal of clinical investigation

Red-Horse K, Rivera J, Schanz A, Zhou Y, Winn V, Kapidzic M, Maltepe E, Okazaki K, Kochman R, Vo KC, Giudice L, Erlebacher A, McCune JM, Stoddart CA, Fisher SJ

Literature watch. Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation.

Lymphatic research and biology

Red-Horse K, Rivera J, Schanz A, Zhou Y, Winn V, Kapidzic M, Maltepe E, Okazaki K, Kochman R, Vo KC, Giudice L, Erlebacher A, McCune JM, Stoddart CA, Fisher SJ

Oxygen, epigenetics and stem cell fate.

Regenerative medicine

Okazaki K, Maltepe E

Hypoxia-inducible factors 1alpha and 2alpha regulate trophoblast differentiation.

Molecular and cellular biology

Cowden Dahl KD, Fryer BH, Mack FA, Compernolle V, Maltepe E, Adelman DM, Carmeliet P, Simon MC

Hypoxia-inducible factor-dependent histone deacetylase activity determines stem cell fate in the placenta.

Development (Cambridge, England)

Maltepe E, Krampitz GW, Okazaki KM, Red-Horse K, Mak W, Simon MC, Fisher SJ

Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses.

Genes & development

Adelman DM, Gertsenstein M, Nagy A, Simon MC, Maltepe E

TRAF4 deficiency leads to tracheal malformation with resulting alterations in air flow to the lungs.

The American journal of pathology

Shiels H, Li X, Schumacker PT, Maltepe E, Padrid PA, Sperling A, Thompson CB, Lindsten T

The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia.

Biochemical and biophysical research communications

Maltepe E, Keith B, Arsham AM, Brorson JR, Simon MC

HIF-1 is essential for multilineage hematopoiesis in the embryo.

Advances in experimental medicine and biology

Adelman DM, Maltepe E, Simon MC

Multilineage embryonic hematopoiesis requires hypoxic ARNT activity.

Genes & development

Adelman DM, Maltepe E, Simon MC

Mitochondrial reactive oxygen species trigger hypoxia-induced transcription.

Proceedings of the National Academy of Sciences of the United States of America

Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT

Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse.

Mechanisms of development

Jain S, Maltepe E, Lu MM, Simon C, Bradfield CA

Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha.

Nature

An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM

Structure of the human type-I interferon gene cluster determined from a YAC clone contig.

Genomics

Díaz MO, Pomykala HM, Bohlander SK, Maltepe E, Malik K, Brownstein B, Olopade OI

The use of methylthioadenosine phosphorylase activity to select for human chromosome 9 in interspecies and intraspecies hybrid cells.

Somatic cell and molecular genetics

Porterfield BW, Pomykala H, Maltepe E, Bohlander SK, Rowley JD, Diaz MO

Mapping of the shortest region of overlap of deletions of the short arm of chromosome 9 associated with human neoplasia.

Genomics

Olopade OI, Bohlander SK, Pomykala H, Maltepe E, Van Melle E, Le Beau MM, Diaz MO