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Article ; Online: Matrix Bound Nanovesicles Have Tissue-Specific Characteristics That Suggest a Regulatory Role.

Turner, Neill J / Quijano, Lina M / Hussey, George S / Jiang, Peng / Badylak, Stephen F

2022 Volume 28, Issue 21-22, Page(s) 879–892

Abstract: Recent studies have identified an extracellular vesicle population that is tightly anchored within the extracellular matrix (ECM) of tissues and organs until released by matrix turnover events. Evidence suggests that these matrix-bound nanovesicles (MBVs) ...

Abstract	Recent studies have identified an extracellular vesicle population that is tightly anchored within the extracellular matrix (ECM) of tissues and organs until released by matrix turnover events. Evidence suggests that these matrix-bound nanovesicles (MBVs) are a ubiquitous component of the ECM, raising questions regarding their tissue-specific identity and their biologic function(s). The primary objective of this study was to examine MBVs isolated from six different tissues and compare their physical and compositional characteristics to determine the common and differentially expressed features. Accordingly, the results of this characterization show that while MBVs are a ubiquitous component of the ECM, they contain a protein and microRNA cargo that is tissue specific. The results furthermore suggest that MBVs have an important role in regulating tissue homeostasis.
MeSH term(s)	Extracellular Matrix/metabolism ; Extracellular Vesicles/metabolism ; Extracellular Matrix Proteins/metabolism ; Phagocytosis ; Cell Communication
Chemical Substances	Extracellular Matrix Proteins
Language	English
Publishing date	2022-10-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2022.0091
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Article ; Online: Transcriptomic Regulation of Macrophages by Matrix-Bound Nanovesicle-Associated Interleukin-33.

Cramer, Madeline / Pineda Molina, Catalina / Hussey, George / Turnquist, Heth R / Badylak, Stephen F

Tissue engineering. Part A

2022 Volume 28, Issue 19-20, Page(s) 867–878

Abstract: The innate immune response, particularly the phenotype of responding macrophages, has significant clinical implications in the remodeling outcome following implantation of biomaterials and engineered tissues. In general, facilitation of an anti- ... ...

Abstract	The innate immune response, particularly the phenotype of responding macrophages, has significant clinical implications in the remodeling outcome following implantation of biomaterials and engineered tissues. In general, facilitation of an anti-inflammatory (M2-like) phenotype is associated with tissue repair and favorable outcomes, whereas pro-inflammatory (M1-like) activation can contribute to chronic inflammation and a classic foreign body response. Biologic scaffolds composed of extracellular matrix (ECM) and, more recently, matrix-bound nanovesicles (MBV) embedded within the ECM are known to direct macrophages toward an anti-inflammatory phenotype and stimulate a constructive remodeling outcome. The mechanisms of MBV-mediated macrophage activation are not fully understood, but interleukin-33 (IL-33) within the MBV appears critical for M2-like activation. Previous work has shown that IL-33 is encapsulated within the lumen of MBV and stimulates phenotypical changes in macrophages independent of its canonical surface receptor stimulation-2 (ST2). In the present study, we used next-generation RNA sequencing to determine the gene signature of macrophages following exposure to MBV with and without intraluminal IL-33. MBV-associated IL-33 instructed an anti-inflammatory phenotype in both wild-type and
MeSH term(s)	Interleukin-33/genetics ; Interleukin-33/metabolism ; Transcriptome/genetics ; Interleukin-1 Receptor-Like 1 Protein/genetics ; Interleukin-1 Receptor-Like 1 Protein/metabolism ; Macrophages/metabolism ; Biocompatible Materials ; Phenotype ; Anti-Inflammatory Agents ; Biological Products/metabolism
Chemical Substances	Interleukin-33 ; Interleukin-1 Receptor-Like 1 Protein ; Biocompatible Materials ; Anti-Inflammatory Agents ; Biological Products
Language	English
Publishing date	2022-08-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2420582-5
ISSN	1937-335X ; 1937-3341
ISSN (online)	1937-335X
ISSN	1937-3341
DOI	10.1089/ten.TEA.2022.0006
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Article ; Online: PhosphoDisco: A Toolkit for Co-regulated Phosphorylation Module Discovery in Phosphoproteomic Data.

Schraink, Tobias / Blumenberg, Lili / Hussey, Grant / George, Sabrina / Miller, Brecca / Mathew, Nithu / González-Robles, Tania J / Sviderskiy, Vladislav / Papagiannakopoulos, Thales / Possemato, Richard / Fenyö, David / Ruggles, Kelly V

Molecular & cellular proteomics : MCP

2023 Volume 22, Issue 8, Page(s) 100596

Abstract: Kinases are key players in cancer-relevant pathways and are the targets of many successful precision cancer therapies. Phosphoproteomics is a powerful approach to study kinase activity and has been used increasingly for the characterization of tumor ... ...

Abstract	Kinases are key players in cancer-relevant pathways and are the targets of many successful precision cancer therapies. Phosphoproteomics is a powerful approach to study kinase activity and has been used increasingly for the characterization of tumor samples leading to the identification of novel chemotherapeutic targets and biomarkers. Finding co-regulated phosphorylation sites which represent potential kinase-substrate sets or members of the same signaling pathway allows us to harness these data to identify clinically relevant and targetable alterations in signaling cascades. Unfortunately, studies have found that databases of co-regulated phosphorylation sites are only experimentally supported in a small number of substrate sets. To address the inherent challenge of defining co-regulated phosphorylation modules relevant to a given dataset, we developed PhosphoDisco, a toolkit for determining co-regulated phosphorylation modules. We applied this approach to tandem mass spectrometry based phosphoproteomic data for breast and non-small cell lung cancer and identified canonical as well as putative new phosphorylation site modules. Our analysis identified several interesting modules in each cohort. Among these was a new cell cycle checkpoint module enriched in basal breast cancer samples and a module of PRKC isozymes putatively co-regulated by CDK12 in lung cancer. We demonstrate that modules defined by PhosphoDisco can be used to further personalized cancer treatment strategies by establishing active signaling pathways in a given patient tumor or set of tumors, and in providing new ways to classify tumors based on signaling activity.
MeSH term(s)	Humans ; Phosphorylation ; Carcinoma, Non-Small-Cell Lung ; Lung Neoplasms ; Signal Transduction ; Tandem Mass Spectrometry
Language	English
Publishing date	2023-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2023.100596
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Article ; Online: Extracellular Vesicles for Regenerative Medicine Applications

Raphael J. Crum / Héctor Capella-Monsonís / Stephen F. Badylak / George S. Hussey

Applied Sciences, Vol 12, Iss 15, p

2022 Volume 7472

Abstract: Tissue engineering and regenerative medicine (TERM) may be defined as a translational discipline focused on the development of novel techniques, devices, and materials to replace or repair injured or diseased tissue and organs. The main approaches ... ...

Abstract	Tissue engineering and regenerative medicine (TERM) may be defined as a translational discipline focused on the development of novel techniques, devices, and materials to replace or repair injured or diseased tissue and organs. The main approaches typically use cells, scaffolds, and signaling molecules, either alone or in combination, to promote repair and regeneration. Although cells are required to create new functional tissue, the source of cells, either from an exogenous allogeneic or autologous source or through the recruitment of endogenous (autologous) cells, is technically challenging and risks the host rejection of new tissue. Regardless of the cell source, these approaches also require appropriate instruction for proliferation, differentiation, and in vivo spatial organization to create new functional tissue. Such instruction is supplied through the microenvironment where cells reside, environments which largely consist of the extracellular matrix (ECM). The specific components of the ECM, and broadly the extracellular space, responsible for promoting tissue regeneration and repair, are not fully understood, however extracellular vesicles (EVs) found in body fluids and solid phases of ECM have emerged as key mediators of tissue regeneration and repair. Additionally, these EVs might serve as potential cell-free tools in TERM to promote tissue repair and regeneration with minimal risk for host rejection and adverse sequelae. The past two decades have shown a substantial interest in understanding the therapeutic role of EVs and their applications in the context of TERM. Therefore, the purpose of this review is to highlight the fundamental characteristics of EVs, the current pre-clinical and clinical applications of EVs in TERM, and the future of EV-based strategies in TERM.
Keywords	tissue engineering ; regenerative medicine ; extracellular vesicle ; Technology ; T ; Engineering (General). Civil engineering (General) ; TA1-2040 ; Biology (General) ; QH301-705.5 ; Physics ; QC1-999 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Extracellular Matrix Bioscaffolds for Building Gastrointestinal Tissue.

Hussey, George S / Cramer, Madeline C / Badylak, Stephen F

Cellular and molecular gastroenterology and hepatology

2018 Volume 5, Issue 1, Page(s) 1–13

Abstract: Regenerative medicine is a rapidly advancing field that uses principles of tissue engineering, developmental biology, stem cell biology, immunology, and bioengineering to reconstruct diseased or damaged tissues. Biologic scaffolds composed of ... ...

Abstract	Regenerative medicine is a rapidly advancing field that uses principles of tissue engineering, developmental biology, stem cell biology, immunology, and bioengineering to reconstruct diseased or damaged tissues. Biologic scaffolds composed of extracellular matrix have shown great promise as an inductive substrate to facilitate the constructive remodeling of gastrointestinal (GI) tissue damaged by neoplasia, inflammatory bowel disease, and congenital or acquired defects. The present review summarizes the preparation and use of extracellular matrix scaffolds for bioengineering of the GI tract, identifies significant advances made in regenerative medicine for the reconstruction of functional GI tissue, and describes an emerging therapeutic approach.
Language	English
Publishing date	2018
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2352-345X
ISSN	2352-345X
DOI	10.1016/j.jcmgh.2017.09.004
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Article ; Online: Immunomodulatory matrix-bound nanovesicles mitigate acute and chronic pristane-induced rheumatoid arthritis.

Crum, Raphael J / Hall, Kelsey / Molina, Catalina Pineda / Hussey, George S / Graham, Emma / Li, Hongshuai / Badylak, Stephen F

NPJ Regenerative medicine

2022 Volume 7, Issue 1, Page(s) 13

Abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti- ... ...

Abstract	Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and destruction of synovial joints affecting ~7.5 million people worldwide. Disease pathology is driven by an imbalance in the ratio of pro-inflammatory vs. anti-inflammatory immune cells, especially macrophages. Modulation of macrophage phenotype, specifically an M1 to M2, pro- to anti-inflammatory transition, can be induced by biologic scaffold materials composed of extracellular matrix (ECM). The ECM-based immunomodulatory effect is thought to be mediated in part through recently identified matrix-bound nanovesicles (MBV) embedded within ECM. Isolated MBV was delivered via intravenous (i.v.) or peri-articular (p.a.) injection to rats with pristane-induced arthritis (PIA). The results of MBV administration were compared to intraperitoneal (i.p.) administration of methotrexate (MTX), the clinical standard of care. Relative to the diseased animals, i.p. MTX, i.v. MBV, and p.a. MBV reduced arthritis scores in both acute and chronic pristane-induced arthritis, decreased synovial inflammation, decreased adverse joint remodeling, and reduced the ratio of synovial and splenic M1 to M2 macrophages (p < 0.05). Both p.a. and i.v. MBV reduced the serum concentration of RA and PIA biomarkers CXCL10 and MCP-3 in the acute and chronic phases of disease (p < 0.05). Flow-cytometry revealed the presence of a systemic CD43hi/His48lo/CD206+, immunoregulatory monocyte population unique to p.a. and i.v. MBV treatment associated with disease resolution. The results show that the therapeutic efficacy of MBV is equal to that of MTX for the management of acute and chronic pristane-induced arthritis and, further, this effect is associated with modulation of local synovial macrophages and systemic myeloid populations.
Language	English
Publishing date	2022-02-02
Publishing country	United States
Document type	Journal Article
ISSN	2057-3995
ISSN (online)	2057-3995
DOI	10.1038/s41536-022-00208-9
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Article ; Online: Alarmins of the extracellular space.

Dziki, Jenna L / Hussey, George / Badylak, Stephen F

Seminars in immunology

2018 Volume 38, Page(s) 33–39

Abstract: The ability of the immune system to discriminate between healthy-self, abnormal-self, and non-self has been attributed mainly to alarmins signaling as "danger signals". It is now evident, however, that alarmins are much more complex and can perform ... ...

Abstract	The ability of the immune system to discriminate between healthy-self, abnormal-self, and non-self has been attributed mainly to alarmins signaling as "danger signals". It is now evident, however, that alarmins are much more complex and can perform specialized functions that can regulate a wide spectrum of processes ranging from propagation of disease to tissue homeostasis. As such, alarmins and their signaling mechanisms are now actively pursued as therapeutic targets. The clinical utility of alarmins requires an understanding of their specific localization. Specifically, many alarmins can function paradoxically depending upon their localization, intra or extracellular. The present review focuses upon alarmin presence and differential expression in the extracellular space versus within the cell and how variation of the localization of alarmins can reveal important mechanistic insights into alarmin functions and their efficacy as biomarkers of disease and therapeutic targets.
MeSH term(s)	Alarmins/immunology ; Alarmins/metabolism ; Animals ; Biomarkers/metabolism ; Extracellular Space/immunology ; Extracellular Space/metabolism ; Homeostasis/immunology ; Humans ; Signal Transduction/immunology
Chemical Substances	Alarmins ; Biomarkers
Language	English
Publishing date	2018-08-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2018.08.004
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Zs.A 2843: Show issues

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Article ; Online: Mitigation of influenza-mediated inflammation by immunomodulatory matrix-bound nanovesicles.

Crum, Raphael J / Huckestien, Brydie R / Dwyer, Gaelen / Mathews, Lisa / Nascari, David G / Hussey, George S / Turnquist, Heth R / Alcorn, John F / Badylak, Stephen F

Science advances

2023 Volume 9, Issue 20, Page(s) eadf9016

Abstract: Cytokine storm describes a life-threatening, systemic inflammatory syndrome characterized by elevated levels of proinflammatory cytokines and immune cell hyperactivation associated with multi-organ dysfunction. Matrix-bound nanovesicles (MBV) are a ... ...

Abstract	Cytokine storm describes a life-threatening, systemic inflammatory syndrome characterized by elevated levels of proinflammatory cytokines and immune cell hyperactivation associated with multi-organ dysfunction. Matrix-bound nanovesicles (MBV) are a subclass of extracellular vesicle shown to down-regulate proinflammatory immune responses. The objective of this study was to assess the efficacy of MBV in mediating influenza-induced acute respiratory distress syndrome and cytokine storm in a murine model. Intravenous administration of MBV decreased influenza-mediated total lung inflammatory cell density, proinflammatory macrophage frequencies, and proinflammatory cytokines at 7 and 21 days following viral inoculation. MBV decreased long-lasting alveolitis and the proportion of lung undergoing inflammatory tissue repair at day 21. MBV increased the proportion of activated anti-viral CD4
MeSH term(s)	Mice ; Animals ; Humans ; Influenza, Human/drug therapy ; SARS-CoV-2 ; COVID-19 ; Cytokine Release Syndrome ; CD8-Positive T-Lymphocytes ; Inflammation/drug therapy ; Cytokines ; Immunity
Chemical Substances	Cytokines
Language	English
Publishing date	2023-05-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adf9016
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Article ; Online: ASO Author Reflections: Predicting the Response of Esophageal Adenocarcinoma to Chemoradiotherapy Before Surgery Using MicroRNA Biomarkers Offers Hope to Improve Outcomes by Tailoring Treatment to Predicted Responses.

Mayne, George C / Watson, David I / Chiam, Karen / Hussey, Damian J

Annals of surgical oncology

2018 Volume 25, Issue Suppl 3, Page(s) 755–756

MeSH term(s)	Adenocarcinoma ; Biomarkers ; Chemoradiotherapy ; Esophageal Neoplasms ; High-Throughput Nucleotide Sequencing ; Humans ; MicroRNAs ; Neoadjuvant Therapy
Chemical Substances	Biomarkers ; MicroRNAs
Language	English
Publishing date	2018-10-25
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1200469-8
ISSN	1534-4681 ; 1068-9265
ISSN (online)	1534-4681
ISSN	1068-9265
DOI	10.1245/s10434-018-6958-8
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Zs.A 4042: Show issues

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Article ; Online: The extracellular matrix of the gastrointestinal tract: a regenerative medicine platform.

Hussey, George S / Keane, Timothy J / Badylak, Stephen F

Nature reviews. Gastroenterology & hepatology

2017 Volume 14, Issue 9, Page(s) 540–552

Abstract: The synthesis and secretion of components that constitute the extracellular matrix (ECM) by resident cell types occur at the earliest stages of embryonic development, and continue throughout life in both healthy and diseased physiological states. The ECM ...

Abstract	The synthesis and secretion of components that constitute the extracellular matrix (ECM) by resident cell types occur at the earliest stages of embryonic development, and continue throughout life in both healthy and diseased physiological states. The ECM consists of a complex mixture of insoluble and soluble functional components that are arranged in a tissue-specific 3D ultrastructure, and it regulates numerous biological processes, including angiogenesis, innervation and stem cell differentiation. Owing to its composition and influence on embryonic development, as well as cellular and organ homeostasis, the ECM is an ideal therapeutic substrate for the repair of damaged or diseased tissues. Biologic scaffold materials that are composed of ECM have been used in various surgical and tissue-engineering applications. The gastrointestinal (GI) tract presents distinct challenges, such as diverse pH conditions and the requirement for motility and nutrient absorption. Despite these challenges, the use of homologous and heterologous ECM bioscaffolds for the focal or segmental reconstruction and regeneration of GI tissue has shown promise in early preclinical and clinical studies. This Review discusses the importance of tissue-specific ECM bioscaffolds and highlights the major advances that have been made in regenerative medicine strategies for the reconstruction of functional GI tissues.
MeSH term(s)	Extracellular Matrix/physiology ; Gastrointestinal Tract/physiology ; Humans ; Models, Biological ; Regenerative Medicine ; Tissue Engineering ; Wound Healing/physiology
Language	English
Publishing date	2017-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2493722-8
ISSN	1759-5053 ; 1759-5045
ISSN (online)	1759-5053
ISSN	1759-5045
DOI	10.1038/nrgastro.2017.76
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