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Article ; Online: Structure and functions of Mer, an innate immune checkpoint.

Ubil, Eric / Zahid, Kashif Rafiq

2023 Volume 14, Page(s) 1244170

Abstract: Immunotherapy is a promising therapeutic tool that promotes the elimination of cancerous cells by a patient's own immune system. However, in the clinical setting, the number of cancer patients benefitting from immunotherapy is limited. Identification and ...

Abstract	Immunotherapy is a promising therapeutic tool that promotes the elimination of cancerous cells by a patient's own immune system. However, in the clinical setting, the number of cancer patients benefitting from immunotherapy is limited. Identification and targeting of other immune subsets, such as tumor-associated macrophages, and alternative immune checkpoints, like Mer, may further limit tumor progression and therapy resistance. In this review, we highlight the key roles of macrophage Mer signaling in immune suppression. We also summarize the role of pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in tumor onset and progression and how Mer structure and activation can be targeted therapeutically to alter activation state. Preclinical and clinical studies focusing on Mer kinase inhibition have demonstrated the potential of targeting this innate immune checkpoint, leading to improved anti-tumor responses and patient outcomes.
MeSH term(s)	Humans ; c-Mer Tyrosine Kinase/metabolism ; Macrophages ; Neoplasms/therapy ; Signal Transduction ; Immunity, Innate
Chemical Substances	c-Mer Tyrosine Kinase (EC 2.7.10.1)
Language	English
Publishing date	2023-10-23
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1244170
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Article ; Online: Mechanisms of Macrophage Plasticity in the Tumor Environment: Manipulating Activation State to Improve Outcomes.

Ricketts, Tiffany Davia / Prieto-Dominguez, Nestor / Gowda, Pramod Sreerama / Ubil, Eric

Frontiers in immunology

2021 Volume 12, Page(s) 642285

Abstract: Macrophages are a specialized class of innate immune cells with multifaceted roles in modulation of the inflammatory response, homeostasis, and wound healing. While developmentally derived or originating from circulating monocytes, naïve macrophages can ... ...

Abstract	Macrophages are a specialized class of innate immune cells with multifaceted roles in modulation of the inflammatory response, homeostasis, and wound healing. While developmentally derived or originating from circulating monocytes, naïve macrophages can adopt a spectrum of context-dependent activation states ranging from pro-inflammatory (classically activated, M1) to pro-wound healing (alternatively activated, M2). Tumors are known to exploit macrophage polarization states to foster a tumor-permissive milieu, particularly by skewing macrophages toward a pro-tumor (M2) phenotype. These pro-tumoral macrophages can support cancer progression by several mechanisms including immune suppression, growth factor production, promotion of angiogenesis and tissue remodeling. By preventing the adoption of this pro-tumor phenotype or reprogramming these macrophages to a more pro-inflammatory state, it may be possible to inhibit tumor growth. Here, we describe types of tumor-derived signaling that facilitate macrophage reprogramming, including paracrine signaling and activation of innate immune checkpoints. We also describe intervention strategies targeting macrophage plasticity to limit disease progression and address their implications in cancer chemo- and immunotherapy.
MeSH term(s)	Animals ; Humans ; Macrophage Activation/immunology ; Macrophages/immunology ; Neoplasms/immunology ; Tumor Escape/immunology ; Tumor Microenvironment/immunology
Language	English
Publishing date	2021-05-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.642285
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Article: Studying the effects of tumor-secreted paracrine ligands on macrophage activation using co-culture with permeable membrane supports

Pittman, Kelly / Earp, Shelton / Ubil, Eric

Journal of visualized experiments. 2019 Nov. 28, , no. 153

2019

Abstract: Tumor-derived paracrine signaling is an overlooked component of local immunosuppression and can lead to a permissive environment for continued cancer growth and metastasis. Paracrine signals can involve cell-cell contact between different cell types, ... ...

Abstract	Tumor-derived paracrine signaling is an overlooked component of local immunosuppression and can lead to a permissive environment for continued cancer growth and metastasis. Paracrine signals can involve cell-cell contact between different cell types, such as PD-L1 expressed on the surface of tumors interacting directly with PD-1 on the surface of T cells, or the secretion of ligands by a tumor cell to affect an immune cell. Here we describe a co-culture method to interrogate the effects of tumor-secreted ligands on immune cell (macrophage) activation. This straightforward procedure utilizes commercially available 0.4 µm polycarbonate membrane permeable supports and standard tissue culture plates. In the process described, macrophages are cultured in the upper chamber and tumor cells in the lower chamber. The presence of the 0.4 µm barrier allows for the study of intercellular signaling without the confounding variable of physical contact, because the two cell types share the same medium and exposure to paracrine ligands. This approach can be combined with others, such as genetic alterations of the macrophage (e.g., isolation from genetic knock-out mice) or tumor (e.g., CRISPR-mediated alterations) to study the role of specific secreted factors and receptors. The approach also lends itself to standard molecular biological analyses such as quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blot analysis, without the need for flow sorting to separate the two cell populations. Enzyme-linked immunosorbent assays (ELISAs) can similarly be utilized to measure secreted ligands to better understand the dynamic interaction of cell signaling in the multiple cell type context. Duration of co-culture can also be varied for the study of temporally regulated events. This co-culture method is a robust tool that facilitates the study of tumor-secreted signals in the immune context.
Keywords	T-lymphocytes ; Western blotting ; coculture ; enzyme-linked immunosorbent assay ; immunosuppression ; ligands ; macrophage activation ; macrophages ; metastasis ; mice ; neoplasm cells ; neoplasms ; paracrine signaling ; quantitative polymerase chain reaction ; receptors ; reverse transcriptase polymerase chain reaction ; secretion ; tissue culture
Language	English
Dates of publication	2019-1128
Size	p. e60453.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/60453
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Article ; Online: Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports.

Pittman, Kelly / Earp, Shelton / Ubil, Eric

Journal of visualized experiments : JoVE

2019 , Issue 153

Abstract	Tumor-derived paracrine signaling is an overlooked component of local immunosuppression and can lead to a permissive environment for continued cancer growth and metastasis. Paracrine signals can involve cell-cell contact between different cell types, such as PD-L1 expressed on the surface of tumors interacting directly with PD-1 on the surface of T cells, or the secretion of ligands by a tumor cell to affect an immune cell. Here we describe a co-culture method to interrogate the effects of tumor-secreted ligands on immune cell (macrophage) activation. This straightforward procedure utilizes commercially available 0.4 µm polycarbonate membrane permeable supports and standard tissue culture plates. In the process described, macrophages are cultured in the upper chamber and tumor cells in the lower chamber. The presence of the 0.4 µm barrier allows for the study of intercellular signaling without the confounding variable of physical contact, because the two cell types share the same medium and exposure to paracrine ligands. This approach can be combined with others, such as genetic alterations of the macrophage (e.g., isolation from genetic knock-out mice) or tumor (e.g., CRISPR-mediated alterations) to study the role of specific secreted factors and receptors. The approach also lends itself to standard molecular biological analyses such as quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blot analysis, without the need for flow sorting to separate the two cell populations. Enzyme-linked immunosorbent assays (ELISAs) can similarly be utilized to measure secreted ligands to better understand the dynamic interaction of cell signaling in the multiple cell type context. Duration of co-culture can also be varied for the study of temporally regulated events. This co-culture method is a robust tool that facilitates the study of tumor-secreted signals in the immune context.
MeSH term(s)	Animals ; Calcium-Binding Proteins/metabolism ; Cell Membrane Permeability ; Coculture Techniques/methods ; Ligands ; Macrophage Activation ; Macrophages/metabolism ; Macrophages/pathology ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/pathology ; Mice ; Paracrine Communication
Chemical Substances	Calcium-Binding Proteins ; Ligands ; Pros1 protein, mouse
Language	English
Publishing date	2019-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/60453
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Article ; Online: Cardiac fibroblast in development and wound healing.

Deb, Arjun / Ubil, Eric

Journal of molecular and cellular cardiology

2014 Volume 70, Page(s) 47–55

Abstract: Cardiac fibroblasts are the most abundant cell type in the mammalian heart and comprise approximately two-thirds of the total number of cardiac cell types. During development, epicardial cells undergo epithelial-mesenchymal-transition to generate cardiac ...

Abstract	Cardiac fibroblasts are the most abundant cell type in the mammalian heart and comprise approximately two-thirds of the total number of cardiac cell types. During development, epicardial cells undergo epithelial-mesenchymal-transition to generate cardiac fibroblasts that subsequently migrate into the developing myocardium to become resident cardiac fibroblasts. Fibroblasts form a structural scaffold for the attachment of cardiac cell types during development, express growth factors and cytokines and regulate proliferation of embryonic cardiomyocytes. In post natal life, cardiac fibroblasts play a critical role in orchestrating an injury response. Fibroblast activation and proliferation early after cardiac injury are critical for maintaining cardiac integrity and function, while the persistence of fibroblasts long after injury leads to chronic scarring and adverse ventricular remodeling. In this review, we discuss the physiologic function of the fibroblast during cardiac development and wound healing, molecular mediators of activation that could be possible targets for drug development for fibrosis and finally the use of reprogramming technologies for reversing scar. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium."
MeSH term(s)	Cicatrix/pathology ; Cicatrix/physiopathology ; Cytokines/biosynthesis ; Extracellular Matrix/chemistry ; Extracellular Matrix/metabolism ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Heart/embryology ; Heart/physiology ; Heart/physiopathology ; Heart Injuries/pathology ; Heart Injuries/physiopathology ; Humans ; Intercellular Signaling Peptides and Proteins/biosynthesis ; Mechanotransduction, Cellular ; Neovascularization, Physiologic ; Wound Healing/physiology
Chemical Substances	Cytokines ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2014-03-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	80157-4
ISSN	1095-8584 ; 0022-2828
ISSN (online)	1095-8584
ISSN	0022-2828
DOI	10.1016/j.yjmcc.2014.02.017
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Article ; Online: Activation of regulatory dendritic cells by Mertk coincides with a temporal wave of apoptosis in neonatal lungs.

Silva-Sanchez, Aaron / Meza-Perez, Selene / Liu, Mingyong / Stone, Sara L / Flores-Romo, Leopoldo / Ubil, Eric / Lund, Frances E / Rosenberg, Alexander F / Randall, Troy D

Science immunology

2023 Volume 8, Issue 84, Page(s) eadc9081

Abstract: Multiple mechanisms restrain inflammation in neonates, most likely to prevent tissue damage caused by overly robust immune responses against newly encountered pathogens. Here, we identify a population of pulmonary dendritic cells (DCs) that express ... ...

Abstract	Multiple mechanisms restrain inflammation in neonates, most likely to prevent tissue damage caused by overly robust immune responses against newly encountered pathogens. Here, we identify a population of pulmonary dendritic cells (DCs) that express intermediate levels of CD103 (CD103
MeSH term(s)	Mice ; Animals ; CD8-Positive T-Lymphocytes ; c-Mer Tyrosine Kinase/metabolism ; Dendritic Cells ; Lung ; Pneumonia ; Apoptosis
Chemical Substances	c-Mer Tyrosine Kinase (EC 2.7.10.1) ; Mertk protein, mouse (EC 2.7.10.1)
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Journal Article
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.adc9081
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Article ; Online: Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response.

Ubil, Eric / Caskey, Laura / Holtzhausen, Alisha / Hunter, Debra / Story, Charlotte / Earp, H Shelton

The Journal of clinical investigation

2018 Volume 128, Issue 6, Page(s) 2356–2369

Abstract: Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor ... ...

Abstract	Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor cells with CRISPR-based deletion of Pros1 failed to inhibit M1 polarization. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice. In addition, several other murine and human tumor cell lines suppressed macrophage M1 cytokine expression induced by IFN-γ and LPS. Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival. TAM activation can also inhibit TLR-mediated M1 polarization. Treatment with resiquimod, a TLR7/8 agonist, did not improve survival in mice bearing Pros1-secreting tumors but doubled survival for Pros1-deleted tumors. The tumor-derived Pros1 immune suppressive system, like PD-L1, was cytokine responsive, with IFN-γ inducing Pros1 transcription and secretion. Inhibition of Pros1/TAM interaction represents a potential novel strategy to block tumor-derived immune suppression.
MeSH term(s)	Animals ; B7-H1 Antigen/genetics ; B7-H1 Antigen/immunology ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Cytokines/genetics ; Cytokines/immunology ; Humans ; Imidazoles/pharmacology ; Macrophages/immunology ; Macrophages/pathology ; Membrane Glycoproteins/agonists ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; Mice ; Mice, Knockout ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/pathology ; Toll-Like Receptor 7/agonists ; Toll-Like Receptor 7/genetics ; Toll-Like Receptor 7/immunology ; Toll-Like Receptor 8/agonists ; Toll-Like Receptor 8/genetics ; Toll-Like Receptor 8/immunology
Chemical Substances	B7-H1 Antigen ; Carrier Proteins ; Cd274 protein, mouse ; Cytokines ; Imidazoles ; Membrane Glycoproteins ; Pros1 protein, mouse ; TLR8 protein, mouse ; Tlr7 protein, mouse ; Toll-Like Receptor 7 ; Toll-Like Receptor 8 ; resiquimod (V3DMU7PVXF)
Language	English
Publishing date	2018-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI97354
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Article ; Online: TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti-PD-1 Therapy in Melanoma.

Holtzhausen, Alisha / Harris, William / Ubil, Eric / Hunter, Debra M / Zhao, Jichen / Zhang, Yuewei / Zhang, Dehui / Liu, Qingyang / Wang, Xiaodong / Graham, Douglas K / Frye, Stephen V / Earp, H Shelton

Cancer immunology research

2019 Volume 7, Issue 10, Page(s) 1672–1686

Abstract: Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) ... ...

Abstract	Myeloid cell receptor tyrosine kinases TYRO3, AXL, and MERTK and their ligands, GAS6 and PROTEIN S, physiologically suppress innate immune responses, including in the tumor microenvironment. Here, we showed that myeloid-derived suppressor cells (MDSC) dramatically upregulated TYRO3, AXL, and MERTK and their ligands [monocytic MDSCs (M-MDSC)>20-fold, polymorphonuclear MDSCs (PMN-MDSC)>15-fold] in tumor-bearing mice. MDSCs from tumor-bearing
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Animals ; Antineoplastic Agents, Immunological/pharmacology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Female ; Healthy Volunteers ; Humans ; Male ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Myeloid-Derived Suppressor Cells/drug effects ; Myeloid-Derived Suppressor Cells/immunology ; Myeloid-Derived Suppressor Cells/metabolism ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/metabolism ; Tumor Microenvironment ; Young Adult ; c-Mer Tyrosine Kinase/metabolism
Chemical Substances	Antineoplastic Agents, Immunological ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; TYRO3 protein, human (EC 2.7.10.1) ; axl receptor tyrosine kinase (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1)
Language	English
Publishing date	2019-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-19-0008
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Article ; Online: MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression.

Jiang, Yao / Zhang, Yanqiong / Leung, Janet Y / Fan, Cheng / Popov, Konstantin I / Su, Siyuan / Qian, Jiayi / Wang, Xiaodong / Holtzhausen, Alisha / Ubil, Eric / Xiang, Yang / Davis, Ian / Dokholyan, Nikolay V / Wu, Gang / Perou, Charles M / Kim, William Y / Earp, H Shelton / Liu, Pengda

Nature communications

2019 Volume 10, Issue 1, Page(s) 1515

Abstract: Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, ...

Abstract	Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt's movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets.
MeSH term(s)	Animals ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Proliferation/physiology ; Female ; HEK293 Cells ; HeLa Cells ; Heterografts ; Humans ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Mice ; Mice, Nude ; Mutation ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; c-Mer Tyrosine Kinase/metabolism
Chemical Substances	Cell Cycle Proteins ; SAV1 protein, human ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; MERTK protein, human (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1) ; Hippo protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2019-04-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-09233-7
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Article ; Online: Mesenchymal-endothelial transition contributes to cardiac neovascularization.

Ubil, Eric / Duan, Jinzhu / Pillai, Indulekha C L / Rosa-Garrido, Manuel / Wu, Yong / Bargiacchi, Francesca / Lu, Yan / Stanbouly, Seta / Huang, Jie / Rojas, Mauricio / Vondriska, Thomas M / Stefani, Enrico / Deb, Arjun

Nature

2014 Volume 514, Issue 7524, Page(s) 585–590

Abstract: Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is ... ...

Abstract	Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial-cell-like phenotype after acute ischaemic cardiac injury. Fibroblast-derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast-derived endothelial cells, reduces post-infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal-to-endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.
MeSH term(s)	Animals ; Cell Transdifferentiation ; Coronary Vessels/cytology ; Coronary Vessels/growth & development ; Endothelial Cells/cytology ; Female ; Fibroblasts/cytology ; In Vitro Techniques ; Male ; Mesoderm/cytology ; Mice ; Myocardial Ischemia/pathology ; Neovascularization, Physiologic ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2014-10-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature13839
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