Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes.

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2016-03-01

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Abstract

AIMS: The differentiation of embryonic stem (ES) cells into energetically efficient cardiomyocytes contributes to functional cardiac repair and is envisioned to ameliorate progressive degenerative cardiac diseases. Advanced cell maturation strategies are therefore needed to create abundant mature cardiomyocytes. In this study, we tested whether the redox-sensitive heme oxygenase-1/carbon monoxide (HO-1/CO) system, operating through mitochondrial biogenesis, acts as a mechanism for ES cell differentiation and cardiomyocyte maturation. RESULTS: Manipulation of HO-1/CO to enhance mitochondrial biogenesis demonstrates a direct pathway to ES cell differentiation and maturation into beating cardiomyocytes that express adult structural markers. Targeted HO-1/CO interventions up- and downregulate specific cardiogenic transcription factors, transcription factor Gata4, homeobox protein Nkx-2.5, heart- and neural crest derivatives-expressed protein 1, and MEF2C. HO-1/CO overexpression increases cardiac gene expression for myosin regulatory light chain 2, atrial isoform, MLC2v, ANP, MHC-β, and sarcomere α-actinin and the major mitochondrial fusion regulators, mitofusin 2 and MICOS complex subunit Mic60. This promotes structural mitochondrial network expansion and maturation, thereby supporting energy provision for beating embryoid bodies. These effects are prevented by silencing HO-1 and by mitochondrial reactive oxygen species scavenging, while disruption of mitochondrial biogenesis and mitochondrial DNA depletion by loss of mitochondrial transcription factor A compromise infrastructure. This leads to failure of cardiomyocyte differentiation and maturation and contractile dysfunction. INNOVATION: The capacity to augment cardiomyogenesis via a defined mitochondrial pathway has unique therapeutic potential for targeting ES cell maturation in cardiac disease. CONCLUSION: Our findings establish the HO-1/CO system and redox regulation of mitochondrial biogenesis as essential factors in ES cell differentiation as well as in the subsequent maturation of these cells into functional cardiac cells.

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10.1089/ars.2015.6342

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Suliman, Hagir B, Fabio Zobi and Claude A Piantadosi (2016). Heme Oxygenase-1/Carbon Monoxide System and Embryonic Stem Cell Differentiation and Maturation into Cardiomyocytes. Antioxid Redox Signal, 24(7). pp. 345–360. 10.1089/ars.2015.6342 Retrieved from https://hdl.handle.net/10161/13986.

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Scholars@Duke

Suliman

Hagir B. Suliman

Associate Professor in Anesthesiology

Dr. Suliman is an expert in the molecular and cell biology of mammalian diseases, particularly in the molecular regulation of oxidant inflammatory responses in the heart and lung. She has a strong interest and expertise in the transcriptional control of cell metabolism, especially mitochondrial biogenesis and mitochondrial-mediated apoptosis and necrosis. Her recent publications have focused on the redox-regulation of nuclear transcription factors involved in both mitochondrial biogenesis and cellular adaptation to oxidative and nitrosative stress. Specifically, she has undertaken promoter analyses of nuclear respiratory factors-1 and -2 that indicate that these transcription factor genes are controlled by redox-regulated signaling networks activated by reactive oxygen and nitrogen species, and carbon monoxide. Dr. Suliman and her colleagues have reported that the cancer chemotherapeutic, doxorubicin, disrupts cardiac mitochondrial biogenesis through mitochondrial oxidant production, which promotes intrinsic apoptosis, while heme oxygenase-1 up-regulates adaptive mitochondrial biogenesis and opposes apoptosis through close regulation of mitochondrial ROS signaling by physiological CO production, thus forestalling fibrosis and cardiomyopathy. Most recently I have been defining the role of mitochondrial transcription factors in regulating cell survival, proliferation and differentiation including in embryonic stem cells and pluripotent cells.

Piantadosi

Claude Anthony Piantadosi

Professor Emeritus of Medicine

Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species transmit biological signals involved in the maintenance of energy metabolism and mitochondrial health, but also contribute to pathogenesis and to the resolution of tissue injury.

Clinically, ALI and the related syndrome of multiple organ failure has a high mortality, which is related to the host inflammatory response, but is not well understood scientifically; thus, the laboratory is devoted to understanding these mechanisms in the context of the host response to relevant but well-controlled experimental manipulations including hyperoxia, bacterial infections, toxic drugs, and cytokine/chemokine signals. The approach relies on animal models, mainly transgenic and knockout mice, and cell models, especially lung and heart cells to evaluate and understand the physiology, pathology, and cell and molecular biology of the injury responses, to test independent and integrated mechanisms, and to devise interventions to prevent damage.

Apart from the lung, significant work is devoted to understanding damage to the heart, brain, liver, and kidney caused by these immune mechanisms, specifically emphasizing the role of mitochondria, key targets and sources of oxidative damage. This damage compromises their ability to support energy homeostasis and advanced cellular functions, and impacts on the important roles these organelles play in cell death by apoptosis and necrosis as well as in the resolution of cellular damage and inflammation.


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