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Article ; Online: A Heart of Stone: Cardiac Fibroblasts Turn to Bone in Calcified Hearts.

Ivey, Kathryn N

2017 Volume 20, Issue 2, Page(s) 151–152

Abstract: The identity of the cells and molecular events driving deleterious calcification of heart muscle remains elusive. In this issue of Cell Stem Cell, Pillai et al. (2017) report that cardiac fibroblasts respond to injury by adopting an osteogenic cell fate ... ...

Abstract	The identity of the cells and molecular events driving deleterious calcification of heart muscle remains elusive. In this issue of Cell Stem Cell, Pillai et al. (2017) report that cardiac fibroblasts respond to injury by adopting an osteogenic cell fate and creating damaging calcific deposits, which can be prevented by inhibiting the activated mineralization process.
MeSH term(s)	Bone and Bones ; Calcinosis ; Cell Differentiation ; Fibroblasts ; Humans ; Osteogenesis
Language	English
Publishing date	2017--02
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2017.01.003
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Article ; Online: microRNAs as Developmental Regulators.

Ivey, Kathryn N / Srivastava, Deepak

Cold Spring Harbor perspectives in biology

2015 Volume 7, Issue 7, Page(s) a008144

Abstract: The field of miRNA biology is relatively young, but its impact on our understanding of the regulation of a wide array of cell functions is far-reaching. The importance of miRNAs in development has become nearly ubiquitous, with miRNAs contributing to ... ...

Abstract	The field of miRNA biology is relatively young, but its impact on our understanding of the regulation of a wide array of cell functions is far-reaching. The importance of miRNAs in development has become nearly ubiquitous, with miRNAs contributing to development of most cells and organs. Although miRNAs are clearly interwoven into known regulatory networks that control cell development, the specific modalities by which they intersect are often quite distinct and cleverly achieved. The frequently emerging theme of feed-back and feed-forward loops to either counterbalance or reinforce the gene programs that they influence is a common thread. Many of these examples of miRNAs as developmental regulators are presently found in organs with different miRNAs and targets, whereas novel, unexpected themes emerge in the context of mouse development as we learn more about this rapidly developing area of biology.
MeSH term(s)	Animals ; Bone Development/genetics ; Cell Differentiation/genetics ; Gastrulation/genetics ; Gene Expression Regulation, Developmental ; Hematopoiesis/genetics ; Mice ; MicroRNAs/chemistry ; MicroRNAs/metabolism ; MicroRNAs/physiology ; Models, Genetic ; Muscle Development/genetics ; Nervous System/embryology ; Signal Transduction
Chemical Substances	MicroRNAs
Language	English
Publishing date	2015-07-01
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a008144
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Article ; Online: The Lizard Gut Microbiome Changes with Temperature and Is Associated with Heat Tolerance.

Moeller, Andrew H / Ivey, Kathleen / Cornwall, Margaret B / Herr, Kathryn / Rede, Jordan / Taylor, Emily N / Gunderson, Alex R

Applied and environmental microbiology

2020 Volume 86, Issue 17

Abstract: Vertebrates harbor trillions of microorganisms in the gut, collectively termed the gut microbiota, which affect a wide range of host functions. Recent experiments in lab-reared vertebrates have shown that changes in environmental temperature can induce ... ...

Abstract	Vertebrates harbor trillions of microorganisms in the gut, collectively termed the gut microbiota, which affect a wide range of host functions. Recent experiments in lab-reared vertebrates have shown that changes in environmental temperature can induce shifts in the gut microbiota, and in some cases these shifts have been shown to affect host thermal physiology. However, there is a lack of information about the effects of temperature on the gut microbiota of wild-caught vertebrates. Moreover, in ectotherms, which are particularly vulnerable to changing temperature regimens, the extent to which microbiota composition is shaped by temperature and associated with host thermal tolerance has not been investigated. To address these issues, we monitored the gut microbiota composition of wild-caught western fence lizards (
MeSH term(s)	Animals ; Bacteria/classification ; California ; Female ; Gastrointestinal Microbiome/physiology ; Lizards/microbiology ; Lizards/physiology ; Male ; Temperature ; Thermotolerance
Language	English
Publishing date	2020-08-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	223011-2
ISSN	1098-5336 ; 0099-2240
ISSN (online)	1098-5336
ISSN	0099-2240
DOI	10.1128/AEM.01181-20
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Article ; Online: AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy.

Wu, Iris / Zeng, Aliya / Greer-Short, Amara / Aycinena, J Alex / Tefera, Anley E / Shenwai, Reva / Farshidfar, Farshad / Van Pell, Melissa / Xu, Emma / Reid, Chris / Rodriguez, Neshel / Lim, Beatriz / Chung, Tae Won / Woods, Joseph / Scott, Aquilla / Jones, Samantha / Dee-Hoskins, Cristina / Gutierrez, Carolina G / Madariaga, Jessie /

Robinson, Kevin / Hatter, Yolanda / Butler, Renee / Steltzer, Stephanie / Ho, Jaclyn / Priest, James R / Song, Xiaomei / Jing, Frank / Green, Kristina / Ivey, Kathryn N / Hoey, Timothy / Yang, Jin / Yang, Zhihong Jane

Communications medicine

2024 Volume 4, Issue 1, Page(s) 38

Abstract: Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the ... ...

Abstract	Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. Methods: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. Results: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. Conclusions: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.
Language	English
Publishing date	2024-03-18
Publishing country	England
Document type	Journal Article
ISSN	2730-664X
ISSN (online)	2730-664X
DOI	10.1038/s43856-024-00450-w
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Article ; Online: The multi-lineage transcription factor ISL1 controls cardiomyocyte cell fate through interaction with NKX2.5.

Maven, Bonnie E J / Gifford, Casey A / Weilert, Melanie / Gonzalez-Teran, Barbara / Hüttenhain, Ruth / Pelonero, Angelo / Ivey, Kathryn N / Samse-Knapp, Kaitlen / Kwong, Wesley / Gordon, David / McGregor, Michael / Nishino, Tomohiro / Okorie, Eyuche / Rossman, Sage / Costa, Mauro W / Krogan, Nevan J / Zeitlinger, Julia / Srivastava, Deepak

Stem cell reports

2023 Volume 18, Issue 11, Page(s) 2138–2153

Abstract: Congenital heart disease often arises from perturbations of transcription factors (TFs) that guide cardiac development. ISLET1 (ISL1) is a TF that influences early cardiac cell fate, as well as differentiation of other cell types including motor neuron ... ...

Abstract	Congenital heart disease often arises from perturbations of transcription factors (TFs) that guide cardiac development. ISLET1 (ISL1) is a TF that influences early cardiac cell fate, as well as differentiation of other cell types including motor neuron progenitors (MNPs) and pancreatic islet cells. While lineage specificity of ISL1 function is likely achieved through combinatorial interactions, its essential cardiac interacting partners are unknown. By assaying ISL1 genomic occupancy in human induced pluripotent stem cell-derived cardiac progenitors (CPs) or MNPs and leveraging the deep learning approach BPNet, we identified motifs of other TFs that predicted ISL1 occupancy in each lineage, with NKX2.5 and GATA motifs being most closely associated to ISL1 in CPs. Experimentally, nearly two-thirds of ISL1-bound loci were co-occupied by NKX2.5 and/or GATA4. Removal of NKX2.5 from CPs led to widespread ISL1 redistribution, and overexpression of NKX2.5 in MNPs led to ISL1 occupancy of CP-specific loci. These results reveal how ISL1 guides lineage choices through a combinatorial code that dictates genomic occupancy and transcription.
MeSH term(s)	Humans ; Transcription Factors/metabolism ; Myocytes, Cardiac ; LIM-Homeodomain Proteins/genetics ; LIM-Homeodomain Proteins/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Cell Differentiation/genetics ; Homeobox Protein Nkx-2.5/genetics ; Homeobox Protein Nkx-2.5/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism
Chemical Substances	Transcription Factors ; LIM-Homeodomain Proteins ; Homeobox Protein Nkx-2.5 ; Homeodomain Proteins
Language	English
Publishing date	2023-10-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2023.09.014
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Article ; Online: Direct and Delayed Mortality of Ceriodaphnia dubia and Rainbow Trout Following Time-Varying Acute Exposures to Zinc.

Mebane, Christopher A / Ivey, Christopher D / Wang, Ning / Steevens, Jeffery A / Cleveland, Danielle / Elias, Michael C / Justice, James R / Gallagher, Kathryn / Brent, Robert N

Environmental toxicology and chemistry

2021 Volume 40, Issue 9, Page(s) 2484–2498

Abstract: The potential for delayed mortality following short-term episodic pollution events was evaluated by exposing cladocerans (Ceriodaphnia dubia) and rainbow trout (Oncorhynchus mykiss) to zinc (Zn) in various 1- to 48-h and 1- to 96-h exposures, ... ...

Abstract	The potential for delayed mortality following short-term episodic pollution events was evaluated by exposing cladocerans (Ceriodaphnia dubia) and rainbow trout (Oncorhynchus mykiss) to zinc (Zn) in various 1- to 48-h and 1- to 96-h exposures, respectively, followed by transferring the exposed organisms to clean water for up to 47 h for C. dubia and up to 95 h for trout for additional observation. For C. dubia, 1-h exposures of up to 3790 µg Zn/L never resulted in mortality during the actual Zn exposures, but by 48 h, a 1-h exposure to 114 µg/L, a concentration similar to the present US national water quality acute criterion for the test water conditions, ultimately killed 70% of C. dubia. With C. dubia, the speed of action of Zn toxicity was faster for intermediate concentrations than for the highest concentrations tested. For rainbow trout, pronounced delayed mortalities by 96 h only occurred following ≥8-h exposures. For both species, ultimate mortalities from Zn exposures ≤8 h mostly presented as delayed mortalities, whereas for exposures ≥24 h, almost all ultimate mortalities presented during the actual exposure periods. With Zn, risks of delayed mortality following exposures to all concentrations tested were much greater for the more sensitive, small-bodied invertebrate (C. dubia) than for the less sensitive, larger-bodied fish (rainbow trout). These results, along with previous studies, show that delayed mortality is an important consideration in evaluating risks to aquatic organisms from brief, episodic exposures to some substances. Environ Toxicol Chem 2021;40:2484-2498. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
MeSH term(s)	Animals ; Cladocera ; Oncorhynchus mykiss ; Water Pollutants, Chemical/analysis ; Water Pollutants, Chemical/toxicity ; Water Quality ; Zinc/toxicity
Chemical Substances	Water Pollutants, Chemical ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2021-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	46234-2
ISSN	1552-8618 ; 0730-7268
ISSN (online)	1552-8618
ISSN	0730-7268
DOI	10.1002/etc.5131
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Article ; Online: MicroRNAs as regulators of differentiation and cell fate decisions.

Ivey, Kathryn N / Srivastava, Deepak

Cell stem cell

2010 Volume 7, Issue 1, Page(s) 36–41

Abstract: Unique expression domains, targets, and gain- and loss-of-function phenotypes of particular microRNAs have important implications for directed differentiation of stem cell populations and suppression of undesired cell types. We discuss this emerging ... ...

Abstract	Unique expression domains, targets, and gain- and loss-of-function phenotypes of particular microRNAs have important implications for directed differentiation of stem cell populations and suppression of undesired cell types. We discuss this emerging topic, in part using muscle differentiation as a paradigm, and highlight common themes and unique modalities by which microRNAs exert their lineage-promoting or differentiation effects on multiple tissues.
MeSH term(s)	Animals ; Cell Cycle/genetics ; Cell Cycle/physiology ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Lineage/genetics ; Cell Lineage/physiology ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/metabolism ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Models, Biological
Chemical Substances	MicroRNAs
Language	English
Publishing date	2010-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2010.06.012
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Article: Direct and Delayed Mortality of Ceriodaphnia dubia and Rainbow Trout Following Time‐Varying Acute Exposures to Zinc

Mebane, Christopher A. / Ivey, Christopher D. / Wang, Ning / Steevens, Jeffery A. / Cleveland, Danielle / Elias, Michael C. / Justice, James R. / Gallagher, Kathryn / Brent, Robert N.

Environmental toxicology and chemistry. 2021 Sept., v. 40, no. 9

2021

Abstract: The potential for delayed mortality following short‐term episodic pollution events was evaluated by exposing cladocerans (Ceriodaphnia dubia) and rainbow trout (Oncorhynchus mykiss) to zinc (Zn) in various 1‐ to 48‐h and 1‐ to 96‐h exposures, ... ...

Abstract	The potential for delayed mortality following short‐term episodic pollution events was evaluated by exposing cladocerans (Ceriodaphnia dubia) and rainbow trout (Oncorhynchus mykiss) to zinc (Zn) in various 1‐ to 48‐h and 1‐ to 96‐h exposures, respectively, followed by transferring the exposed organisms to clean water for up to 47 h for C. dubia and up to 95 h for trout for additional observation. For C. dubia, 1‐h exposures of up to 3790 µg Zn/L never resulted in mortality during the actual Zn exposures, but by 48 h, a 1‐h exposure to 114 µg/L, a concentration similar to the present US national water quality acute criterion for the test water conditions, ultimately killed 70% of C. dubia. With C. dubia, the speed of action of Zn toxicity was faster for intermediate concentrations than for the highest concentrations tested. For rainbow trout, pronounced delayed mortalities by 96 h only occurred following ≥8‐h exposures. For both species, ultimate mortalities from Zn exposures ≤8 h mostly presented as delayed mortalities, whereas for exposures ≥24 h, almost all ultimate mortalities presented during the actual exposure periods. With Zn, risks of delayed mortality following exposures to all concentrations tested were much greater for the more sensitive, small‐bodied invertebrate (C. dubia) than for the less sensitive, larger‐bodied fish (rainbow trout). These results, along with previous studies, show that delayed mortality is an important consideration in evaluating risks to aquatic organisms from brief, episodic exposures to some substances. Environ Toxicol Chem 2021;40:2484–2498. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Keywords	Ceriodaphnia dubia ; Oncorhynchus mykiss ; chemistry ; ecotoxicology ; invertebrates ; mortality ; pollution ; toxicity ; trout ; water quality
Language	English
Dates of publication	2021-09
Size	p. 2484-2498.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	46234-2
ISSN	1552-8618 ; 0730-7268
ISSN (online)	1552-8618
ISSN	0730-7268
DOI	10.1002/etc.5131
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Article ; Online: Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

Zhou, Huanyu / Yang, Jin / Srinath, Chetan / Zeng, Aliya / Wu, Iris / Leon, Elena C / Qureshi, Tawny Neal / Reid, Christopher A / Nettesheim, Emily R / Xu, Emma / Duclos, Zoe / Mohamed, Tamer M A / Farshidfar, Farshad / Fejes, Anthony / Liu, Jun / Jones, Samantha / Feathers, Charles / Chung, Tae Won / Jing, Frank /

Prince, William S / Lin, JianMin / Yu, Pengzhi / Srivastava, Deepak / Hoey, Timothy / Ivey, Kathryn N / Lombardi, Laura M

Circulation

2023 Volume 148, Issue 14, Page(s) 1099–1112

Abstract: Background: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction ... ...

Abstract	Background: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. Methods: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. Results: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. Conclusions: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.
MeSH term(s)	Rats ; Mice ; Humans ; Animals ; Dependovirus/genetics ; Myocytes, Cardiac/metabolism ; Myocardial Infarction/therapy ; Myocardial Infarction/drug therapy ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Genetic Therapy/methods ; Green Fluorescent Proteins/genetics ; Cellular Reprogramming ; Fibroblasts/metabolism
Chemical Substances	MicroRNAs ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2023-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.122.061542
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Article ; Online: The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1.

Zhu, Jun-Yi / Heidersbach, Amy / Kathiriya, Irfan S / Garay, Bayardo I / Ivey, Kathryn N / Srivastava, Deepak / Han, Zhe / King, Isabelle N

Development (Cambridge, England)

2017 Volume 144, Issue 5, Page(s) 866–875

Abstract: ... miR- ... ...

Abstract	miR-1
MeSH term(s)	3' Untranslated Regions ; Actin Cytoskeleton/metabolism ; Actins/metabolism ; Animals ; Body Patterning ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/growth & development ; Drosophila melanogaster/metabolism ; Green Fluorescent Proteins/metabolism ; Heart/physiology ; MicroRNAs/metabolism ; Nedd4 Ubiquitin Protein Ligases ; Phenotype ; Phosphorylation ; Protein Transport ; Receptors, Notch/metabolism ; Signal Transduction ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; Wings, Animal/metabolism
Chemical Substances	3' Untranslated Regions ; Actins ; Drosophila Proteins ; MIRN1 microRNA, Drosophila ; MicroRNAs ; Receptors, Notch ; Green Fluorescent Proteins (147336-22-9) ; Nedd4 Ubiquitin Protein Ligases (EC 2.3.2.26) ; Nedd4 protein, Drosophila (EC 2.3.2.26) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2017--01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.140368
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