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Article ; Online: Blood Vessel Organoids for Development and Disease.

Salewskij, Kirill / Penninger, Josef M

2023 Volume 132, Issue 4, Page(s) 498–510

Abstract: Despite enormous advances, cardiovascular disorders are still a major threat to global health and are responsible for one-third of deaths worldwide. Research for new therapeutics and the investigation of their effects on vascular parameters is often ... ...

Abstract	Despite enormous advances, cardiovascular disorders are still a major threat to global health and are responsible for one-third of deaths worldwide. Research for new therapeutics and the investigation of their effects on vascular parameters is often limited by species-specific pathways and a lack of high-throughput methods. The complex 3-dimensional environment of blood vessels, intricate cellular crosstalks, and organ-specific architectures further complicate the quest for a faithful human in vitro model. The development of novel organoid models of various tissues such as brain, gut, and kidney signified a leap for the field of personalized medicine and disease research. By utilizing either embryonic- or patient-derived stem cells, different developmental and pathological mechanisms can be modeled and investigated in a controlled in vitro environment. We have recently developed self-organizing human capillary blood vessel organoids that recapitulate key processes of vasculogenesis, angiogenesis, and diabetic vasculopathy. Since then, this organoid system has been utilized as a model for other disease processes, refined, and adapted for organ specificity. In this review, we will discuss novel and alternative approaches to blood vessel engineering and explore the cellular identity of engineered blood vessels in comparison to in vivo vasculature. Future perspectives and the therapeutic potential of blood vessel organoids will be discussed.
MeSH term(s)	Humans ; Organoids/metabolism ; Pluripotent Stem Cells/metabolism ; Brain
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.122.321768
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Article ; Online: RANKL and RANK in Cancer Therapy.

Onji, Masahiro / Penninger, Josef M

Physiology (Bethesda, Md.)

2022 Volume 38, Issue 3

Abstract: Receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) are key regulators of mammalian physiology such as bone metabolism, immune tolerance and antitumor immunity, and mammary gland biology. Here, we explore the multiple functions of RANKL/ ...

Abstract	Receptor activator of nuclear factor-κB (RANK) and its ligand (RANKL) are key regulators of mammalian physiology such as bone metabolism, immune tolerance and antitumor immunity, and mammary gland biology. Here, we explore the multiple functions of RANKL/RANK in physiology and pathophysiology and discuss underlying principles and strategies to modulate the RANKL/RANK pathway as a therapeutic target in immune-mediated cancer treatment.
MeSH term(s)	Animals ; Humans ; Receptor Activator of Nuclear Factor-kappa B/metabolism ; Neoplasms ; RANK Ligand/metabolism ; Mammals
Chemical Substances	Receptor Activator of Nuclear Factor-kappa B ; RANK Ligand
Language	English
Publishing date	2022-12-06
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2158667-6
ISSN	1548-9221 ; 1548-9213
ISSN (online)	1548-9221
ISSN	1548-9213
DOI	10.1152/physiol.00020.2022
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Article: Cardiac regeneration: Options for repairing the injured heart.

Wang, Jun / An, Meilin / Haubner, Bernhard Johannes / Penninger, Josef M

Frontiers in cardiovascular medicine

2023 Volume 9, Page(s) 981982

Abstract: Cardiac regeneration is one of the grand challenges in repairing injured human hearts. Numerous studies of signaling pathways and metabolism on cardiac development and disease pave the way for endogenous cardiomyocyte regeneration. New drug delivery ... ...

Abstract	Cardiac regeneration is one of the grand challenges in repairing injured human hearts. Numerous studies of signaling pathways and metabolism on cardiac development and disease pave the way for endogenous cardiomyocyte regeneration. New drug delivery approaches, high-throughput screening, as well as novel therapeutic compounds combined with gene editing will facilitate the development of potential cell-free therapeutics. In parallel, progress has been made in the field of cell-based therapies. Transplantation of human pluripotent stem cell (hPSC)-derived cardiomyocytes (hPSC-CMs) can partially rescue the myocardial defects caused by cardiomyocyte loss in large animals. In this review, we summarize current cell-based and cell-free regenerative therapies, discuss the importance of cardiomyocyte maturation in cardiac regenerative medicine, and envision new ways of regeneration for the injured heart.
Language	English
Publishing date	2023-01-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2022.981982
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Article ; Online: Angiotensin-converting enzyme 2-at the heart of the COVID-19 pandemic.

Oudit, Gavin Y / Wang, Kaiming / Viveiros, Anissa / Kellner, Max J / Penninger, Josef M

Cell

2023 Volume 186, Issue 5, Page(s) 906–922

Abstract: ACE2 is the indispensable entry receptor for SARS-CoV and SARS-CoV-2. Because of the COVID-19 pandemic, it has become one of the most therapeutically targeted human molecules in biomedicine. ACE2 serves two fundamental physiological roles: as an enzyme, ... ...

Abstract	ACE2 is the indispensable entry receptor for SARS-CoV and SARS-CoV-2. Because of the COVID-19 pandemic, it has become one of the most therapeutically targeted human molecules in biomedicine. ACE2 serves two fundamental physiological roles: as an enzyme, it alters peptide cascade balance; as a chaperone, it controls intestinal amino acid uptake. ACE2's tissue distribution, affected by co-morbidities and sex, explains the broad tropism of coronaviruses and the clinical manifestations of SARS and COVID-19. ACE2-based therapeutics provide a universal strategy to prevent and treat SARS-CoV-2 infections, applicable to all SARS-CoV-2 variants and other emerging zoonotic coronaviruses exploiting ACE2 as their cellular receptor.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2/metabolism ; Angiotensin-Converting Enzyme 2 ; Peptidyl-Dipeptidase A/metabolism ; Pandemics ; Severe acute respiratory syndrome-related coronavirus
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2023-02-02
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2023.01.039
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Article ; Online: Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19.

Kuba, Keiji / Yamaguchi, Tomokazu / Penninger, Josef M

Frontiers in immunology

2021 Volume 12, Page(s) 732690

Abstract: Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS ... ...

Abstract	Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.
MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; COVID-19/pathology ; Cardiovascular System/metabolism ; Down-Regulation ; Humans ; Lung Injury/pathology ; Lung Injury/virology ; Protein Domains/genetics ; Receptors, Virus/metabolism ; Renin-Angiotensin System/physiology ; Respiratory Distress Syndrome/pathology ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Receptors, Virus ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-12-22
Publishing country	Switzerland
Document type	Journal Article ; 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.2021.732690
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Article: Targeting the RANKL/RANK/OPG Axis for Cancer Therapy.

Ming, Jie / Cronin, Shane J F / Penninger, Josef M

Frontiers in oncology

2020 Volume 10, Page(s) 1283

Abstract: RANKL and RANK are expressed in different cell types and tissues throughout the body. They were originally described for their essential roles in bone remodeling and the immune system but have subsequently been shown to provide essential signals from ... ...

Abstract	RANKL and RANK are expressed in different cell types and tissues throughout the body. They were originally described for their essential roles in bone remodeling and the immune system but have subsequently been shown to provide essential signals from regulating mammary gland homeostasis during pregnancy to modulating tumorigenesis. The success of RANKL/RANK research serves as a paragon for translational research from the laboratory to the bedside. The case in point has been the development of Denosumab, a RANKL-blocking monoclonal antibody which has already helped millions of patients suffering from post-menopausal osteoporosis and skeletal related events in cancer. Here we will provide an overview of the pathway from its origins to its clinical relevance in disease, with a special focus on emerging evidence demonstrating the therapeutic value of targeting the RANKL/RANK/OPG axis not only in breast cancer but also as an addition to the cancer immunotherapy arsenal.
Language	English
Publishing date	2020-08-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.01283
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Article ; Online: The Role of Angiotensin Converting Enzyme 2 in Modulating Gut Microbiota, Intestinal Inflammation, and Coronavirus Infection.

Penninger, Josef M / Grant, Maria B / Sung, Joseph J Y

Gastroenterology

2020 Volume 160, Issue 1, Page(s) 39–46

Abstract: The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin converting enzyme 2 was identified as a primary receptor ... ...

Abstract	The role of angiotensin converting enzyme 2 has expanded from regulating the renin angiotensin system to regulating intestinal amino acid homeostasis and the gut microbiome. Recently, angiotensin converting enzyme 2 was identified as a primary receptor for severe acute respiratory syndrome coronaviruses 1 and 2 being expressed in multiple tissues including the luminal surface of the gut. In this brief perspective, we examine the role of angiotensin converting enzyme 2 as the receptor for severe acute respiratory syndrome coronavirus 2 and the impact of coronavirus disease 19 infection on the gut microbiome and on the gut epithelium.
MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; Angiotensin-Converting Enzyme 2/therapeutic use ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; COVID-19/enzymology ; COVID-19/microbiology ; COVID-19/virology ; Feces/microbiology ; Feces/virology ; Gastroenteritis/drug therapy ; Gastroenteritis/enzymology ; Gastroenteritis/microbiology ; Gastroenteritis/virology ; Gastrointestinal Microbiome/drug effects ; Host-Pathogen Interactions ; Humans ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/enzymology ; Intestinal Mucosa/microbiology ; Intestinal Mucosa/virology ; Receptors, Virus/metabolism ; Renin-Angiotensin System ; SARS-CoV-2/drug effects ; SARS-CoV-2/pathogenicity ; Virus Internalization
Chemical Substances	Anti-Inflammatory Agents ; Antiviral Agents ; Receptors, Virus ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Keywords	covid19
Language	English
Publishing date	2020-10-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2020.07.067
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Zs.MO 572: Show issues

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Article: Redirecting Imipramine against Bluetongue Virus Infection: Insights from a Genome-wide Haploid Screening Study.

John, Lijo / Vernersson, Caroline / Kwon, Hyesoo / Elling, Ulrich / Penninger, Josef M / Mirazimi, Ali

Pathogens (Basel, Switzerland)

2022 Volume 11, Issue 5

Abstract: Bluetongue virus (BTV), an arbovirus of ruminants, is a causative agent of numerous epidemics around the world. Due to the emergence of novel reassortant BTV strains and new outbreaks, there is an unmet need for efficacious antivirals. In this study, we ... ...

Abstract	Bluetongue virus (BTV), an arbovirus of ruminants, is a causative agent of numerous epidemics around the world. Due to the emergence of novel reassortant BTV strains and new outbreaks, there is an unmet need for efficacious antivirals. In this study, we used an improved haploid screening platform to identify the relevant host factors for BTV infection. Our screening tool identified and validated the host factor Niemann-Pick C1 (NPC1), a lysosomal membrane protein that is involved in lysosomal cholesterol transport, as a critical factor in BTV infection. This finding prompted us to investigate the possibility of testing imipramine, an antidepressant drug known to inhibit NPC1 function by interfering with intracellular cholesterol trafficking. In this study, we evaluated the sensitivity of BTV to imipramine using in vitro assays. Our results demonstrate that imipramine pretreatment inhibited in vitro replication and progeny release of BTV-4, BTV-8, and BTV-16. Collectively, our findings highlight the importance of NPC1 for BTV infection and recommend the reprofiling of imipramine as a potential antiviral drug against BTV.
Language	English
Publishing date	2022-05-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens11050602
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Article ; Online: Low-density lipoprotein receptor-related protein 1 (LRP1) as an auxiliary host factor for RNA viruses.

Devignot, Stephanie / Sha, Tim Wai / Burkard, Thomas R / Schmerer, Patrick / Hagelkruys, Astrid / Mirazimi, Ali / Elling, Ulrich / Penninger, Josef M / Weber, Friedemann

Life science alliance

2023 Volume 6, Issue 7

Abstract: Viruses with an RNA genome are often the cause of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid insertion-mutagenized mouse embryonic cell library for clones that are resistant to Rift Valley fever ... ...

Abstract	Viruses with an RNA genome are often the cause of zoonotic infections. In order to identify novel pro-viral host cell factors, we screened a haploid insertion-mutagenized mouse embryonic cell library for clones that are resistant to Rift Valley fever virus (RVFV). This screen returned the low-density lipoprotein receptor-related protein 1 (LRP1) as a top hit, a plasma membrane protein involved in a wide variety of cell activities. Inactivation of
MeSH term(s)	Animals ; Humans ; Mice ; Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; COVID-19 ; SARS-CoV-2/genetics ; Rift Valley fever virus/genetics ; Rift Valley fever virus/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Lipoproteins, LDL/metabolism
Chemical Substances	Low Density Lipoprotein Receptor-Related Protein-1 ; RNA, Small Interfering ; Lipoproteins, LDL ; LRP1 protein, human ; Lrp1 protein, mouse
Language	English
Publishing date	2023-04-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302005
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Article ; Online: Implementation of a Drug Screening Platform to Target

Cronin, Shane J F / Davidow, Lance S / Arvanites, Anthony C / Rubin, Lee L / Penninger, Josef M / Woolf, Clifford J

Bio-protocol

2023 Volume 13, Issue 9, Page(s) e4666

Abstract: Management of neuropathic pain is notoriously difficult; current analgesics, including anti-inflammatory- and opioid-based medications, are generally ineffective and can pose serious side effects. There is a need to uncover non-addictive and safe ... ...

Abstract	Management of neuropathic pain is notoriously difficult; current analgesics, including anti-inflammatory- and opioid-based medications, are generally ineffective and can pose serious side effects. There is a need to uncover non-addictive and safe analgesics to combat neuropathic pain. Here, we describe the setup of a phenotypic screen whereby the expression of an algesic gene,
Language	English
Publishing date	2023-05-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4666
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