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Article ; Online: The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID-19?

Hondermarck, Hubert / Bartlett, Nathan W / Nurcombe, Victor

FASEB bioAdvances

2020 Volume 2, Issue 5, Page(s) 296–303

Abstract: Growth factor receptors are known to be involved in the process of viral infection. Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in order to ...

Abstract	Growth factor receptors are known to be involved in the process of viral infection. Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in order to replicate. Thus, repurposing drugs that have initially been developed to target growth factor receptors and their signaling in cancer may prove to be a fast track to effective therapies against emerging new viral infections, including the coronavirus disease 19 (COVID-19).
Keywords	covid19
Language	English
Publishing date	2020-04-11
Publishing country	United States
Document type	Journal Article
ISSN	2573-9832
ISSN (online)	2573-9832
DOI	10.1096/fba.2020-00015
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Rational synthesis of a heparan sulfate saccharide that promotes the activity of BMP2.

Shaffer, Karl J / Smith, Raymond A A / Daines, Alison M / Luo, Xiaoman / Lu, Xiaohua / Tan, Tuan Chun / Le, Bach Q / Schwörer, Ralf / Hinkley, Simon F R / Tyler, Peter C / Nurcombe, Victor / Cool, Simon M

Carbohydrate polymers

2024 Volume 333, Page(s) 121979

Abstract: Heparan sulfate (HS) is a glycosaminoglycan (GAG) found throughout nature and is involved in a wide range of functions including modulation of cell signalling via sequestration of growth factors. Current consensus is that the specificity of HS motifs for ...

Abstract	Heparan sulfate (HS) is a glycosaminoglycan (GAG) found throughout nature and is involved in a wide range of functions including modulation of cell signalling via sequestration of growth factors. Current consensus is that the specificity of HS motifs for protein binding are individual for each protein. Given the structural complexity of HS the synthesis of libraries of these compounds to probe this is not trivial. Herein we present the synthesis of an HS decamer, the design of which was undertaken rationally from previously published data for HS binding to the growth factor BMP-2. The biological activity of this HS decamer was assessed in vitro, showing that it had the ability to both bind BMP-2 and increase its thermal stability as well as enhancing the bioactivity of BMP-2 in vitro in C2C12 cells. At the same time no undesired anticoagulant effect was observed. This decamer was then analysed in vivo in a rabbit model where higher bone formation, bone mineral density (BMD) and trabecular thickness were observed over an empty defect or collagen implant alone. This indicated that the HS decamer was effective in promoting bone regeneration in vivo.
MeSH term(s)	Animals ; Rabbits ; Heparitin Sulfate/chemistry ; Glycosaminoglycans ; Osteogenesis ; Protein Binding ; Bone Regeneration ; Intercellular Signaling Peptides and Proteins/metabolism
Chemical Substances	Heparitin Sulfate (9050-30-0) ; Glycosaminoglycans ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2024-02-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2024.121979
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Article: Heparan Sulfate Proteoglycans: Key Mediators of Stem Cell Function.

Ravikumar, Maanasa / Smith, Raymond Alexander Alfred / Nurcombe, Victor / Cool, Simon M

Frontiers in cell and developmental biology

2020 Volume 8, Page(s) 581213

Abstract: Heparan sulfate proteoglycans (HSPGs) are an evolutionarily ancient subclass of glycoproteins with exquisite structural complexity. They are ubiquitously expressed across tissues and have been found to exert a multitude of effects on cell behavior and ... ...

Abstract	Heparan sulfate proteoglycans (HSPGs) are an evolutionarily ancient subclass of glycoproteins with exquisite structural complexity. They are ubiquitously expressed across tissues and have been found to exert a multitude of effects on cell behavior and the surrounding microenvironment. Evidence has shown that heterogeneity in HSPG composition is crucial to its functions as an essential scaffolding component in the extracellular matrix as well as a vital cell surface signaling co-receptor. Here, we provide an overview of the significance of HSPGs as essential regulators of stem cell function. We discuss the various roles of HSPGs in distinct stem cell types during key physiological events, from development through to tissue homeostasis and regeneration. The contribution of aberrant HSPG production to altered stem cell properties and dysregulated cellular homeostasis characteristic of cancer is also reviewed. Finally, we consider approaches to better understand and exploit the multifaceted functions of HSPGs in influencing stem cell characteristics for cell therapy and associated culture expansion strategies.
Language	English
Publishing date	2020-11-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2020.581213
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Article ; Online: Age-Related Changes in the Inflammatory Status of Human Mesenchymal Stem Cells: Implications for Cell Therapy.

Zhang, Ying / Ravikumar, Maanasa / Ling, Ling / Nurcombe, Victor / Cool, Simon M

Stem cell reports

2021 Volume 16, Issue 4, Page(s) 694–707

Abstract: Human mesenchymal stem/stromal cell (hMSC)-based cell therapies are promising for treating a variety of diseases. The unique immunomodulatory properties of hMSCs have extended their therapeutic potential beyond tissue regeneration. However, extensive pre- ...

Abstract	Human mesenchymal stem/stromal cell (hMSC)-based cell therapies are promising for treating a variety of diseases. The unique immunomodulatory properties of hMSCs have extended their therapeutic potential beyond tissue regeneration. However, extensive pre-clinical culture expansion inevitably drives cells toward replicative "aging" and a consequent decline in quality. These "in vitro-aged" hMSCs resemble biologically aged cells, which have been reported to show senescence signatures, diminished immunosuppressive capacity, and weakened regenerative potential as well as pro-inflammatory features. In this review, we have surveyed the literature to explore the intimate relationship between the inflammatory status of hMSCs and their in vitro aging process. We posit that a shift from an anti-inflammatory to a pro-inflammatory phenotype of culture-expanded hMSCs contributes to a deterioration in their therapeutic efficacy. Potential molecular and cellular mechanisms underpinning this phenomenon have been discussed. We have also highlighted studies that leverage these mechanisms to make culture-expanded hMSCs more amenable for clinical use.
MeSH term(s)	Cell- and Tissue-Based Therapy ; Cellular Senescence ; Clinical Trials as Topic ; Humans ; Immunosuppression Therapy ; Inflammation/pathology ; Mesenchymal Stem Cells/pathology
Language	English
Publishing date	2021-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2021.01.021
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Article ; Online: The role of growth factor receptors in viral infections

Hondermarck, Hubert / Bartlett, Nathan W. / Nurcombe, Victor

FASEB BioAdvances

An opportunity for drug repurposing against emerging viral diseases such as COVID‐19?

2020 Volume 2, Issue 5, Page(s) 296–303

Keywords	covid19
Language	English
Publisher	Wiley
Publishing country	us
Document type	Article ; Online
ISSN	2573-9832
DOI	10.1096/fba.2020-00015
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID-19?

Hondermarck, Hubert / Bartlett, Nathan W. / Nurcombe, Victor

FASEB BioAdvances

Abstract: Abstract Growth factor receptors are known to be involved in the process of viral infection Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in ... ...

Abstract	Abstract Growth factor receptors are known to be involved in the process of viral infection Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in order to replicate Thus, repurposing drugs that have initially been developed to target growth factor receptors and their signaling in cancer may prove to be a fast track to effective therapies against emerging new viral infections, including the coronavirus disease 19 (COVID-19)
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #47522
Database	COVID19

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Article ; Online: FGFR2 accommodates osteogenic cell fate determination in human mesenchymal stem cells.

Zhang, Ying / Ling, Ling / Ajay D/O Ajayakumar, Arya / Eio, Yating Michelle / van Wijnen, Andre J / Nurcombe, Victor / Cool, Simon M

Gene

2022 Volume 818, Page(s) 146199

Abstract: The multilineage differentiation potential of human mesenchymal stem cells (hMSCs) underpins their clinical utility for tissue regeneration. Control of such cell-fate decisions is tightly regulated by different growth factors/cytokines and their cognate ... ...

Abstract	The multilineage differentiation potential of human mesenchymal stem cells (hMSCs) underpins their clinical utility for tissue regeneration. Control of such cell-fate decisions is tightly regulated by different growth factors/cytokines and their cognate receptors. Fibroblast growth factors (FGFs) are among such factors critical for osteogenesis. However, how FGF receptors (FGFRs) help to orchestrate osteogenic progression remains to be fully elucidated. Here, we studied the protein levels of FGFRs during osteogenesis in human adult bone marrow-derived MSCs and discovered a positive correlation between FGFR2 expression and alkaline phosphatase (ALP) activity, an early marker of osteogenesis. Through RNA interference studies, we confirmed the role of FGFR2 in promoting the osteogenic differentiation of hMSCs. Knockdown of FGFR2 resulted in downregulation of pro-osteogenic genes and upregulation of pro-adipogenic genes and adipogenic commitment. Moreover, under osteogenic induction, FGFR2 knockdown resulted in upregulation of Enhancer of Zeste Homolog 2 (EZH2), an epigenetic enzyme that regulates MSC lineage commitment and suppresses osteogenesis. Lastly, we show that serial-passaged hMSCs have reduced FGFR2 expression and impaired osteogenic potential. Our study suggests that FGFR2 is critical for mediating osteogenic fate by regulating the balance of osteo-adipogenic lineage commitment. Therefore, examining FGFR2 levels during serial-passaging of hMSCs may prove useful for monitoring their multipotency.
MeSH term(s)	Alkaline Phosphatase/metabolism ; Cell Lineage ; Cell Proliferation ; Cells, Cultured ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Knockdown Techniques ; Humans ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/metabolism ; Osteogenesis/genetics ; Receptor, Fibroblast Growth Factor, Type 1/metabolism ; Receptor, Fibroblast Growth Factor, Type 2/metabolism
Chemical Substances	EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; FGFR1 protein, human (EC 2.7.10.1) ; FGFR2 protein, human (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 1 (EC 2.7.10.1) ; Receptor, Fibroblast Growth Factor, Type 2 (EC 2.7.10.1) ; Alkaline Phosphatase (EC 3.1.3.1)
Language	English
Publishing date	2022-01-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2022.146199
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Zs.A 1357: Show issues

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Article: FGFR2 accommodates osteogenic cell fate determination in human mesenchymal stem cells

Zhang, Ying / Ling, Ling / Ajay D/O Ajayakumar, Arya / Eio, Yating Michelle / van Wijnen, Andre J. / Nurcombe, Victor / Cool, Simon M.

Gene. 2022 Apr. 15, v. 818

2022

Abstract	The multilineage differentiation potential of human mesenchymal stem cells (hMSCs) underpins their clinical utility for tissue regeneration. Control of such cell-fate decisions is tightly regulated by different growth factors/cytokines and their cognate receptors. Fibroblast growth factors (FGFs) are among such factors critical for osteogenesis. However, how FGF receptors (FGFRs) help to orchestrate osteogenic progression remains to be fully elucidated. Here, we studied the protein levels of FGFRs during osteogenesis in human adult bone marrow-derived MSCs and discovered a positive correlation between FGFR2 expression and alkaline phosphatase (ALP) activity, an early marker of osteogenesis. Through RNA interference studies, we confirmed the role of FGFR2 in promoting the osteogenic differentiation of hMSCs. Knockdown of FGFR2 resulted in downregulation of pro-osteogenic genes and upregulation of pro-adipogenic genes and adipogenic commitment. Moreover, under osteogenic induction, FGFR2 knockdown resulted in upregulation of Enhancer of Zeste Homolog 2 (EZH2), an epigenetic enzyme that regulates MSC lineage commitment and suppresses osteogenesis. Lastly, we show that serial-passaged hMSCs have reduced FGFR2 expression and impaired osteogenic potential. Our study suggests that FGFR2 is critical for mediating osteogenic fate by regulating the balance of osteo-adipogenic lineage commitment. Therefore, examining FGFR2 levels during serial-passaging of hMSCs may prove useful for monitoring their multipotency.
Keywords	RNA interference ; adults ; alkaline phosphatase ; bone formation ; cell differentiation ; cytokines ; epigenetics ; fibroblast growth factor receptor 2 ; fibroblasts ; genes ; humans ; tissue repair
Language	English
Dates of publication	2022-0415
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	391792-7
ISSN	1879-0038 ; 0378-1119
ISSN (online)	1879-0038
ISSN	0378-1119
DOI	10.1016/j.gene.2022.146199
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Vascular Cells and Tissue Constructs Derived from Human Pluripotent Stem Cells for Toxicological Screening.

Titmarsh, Drew M / Nurcombe, Victor / Cheung, Christine / Cool, Simon M

Stem cells and development

2019 Volume 28, Issue 20, Page(s) 1347–1364

Abstract: The ability of human stem cells to generate somatic cell lineages makes them ideal candidates for use in toxicological testing and eventually, preclinical drug development. Such resources would support an evolution away from human primary cells or ... ...

Abstract	The ability of human stem cells to generate somatic cell lineages makes them ideal candidates for use in toxicological testing and eventually, preclinical drug development. Such resources would support an evolution away from human primary cells or research animal models, which suffer from variability and poor predictability, toward off-the-shelf assays of chemical toxicity and drug efficacy using human cells and tissues. To this end, we generated vascular cell populations (smooth muscle cells and endothelial cells) from human pluripotent stem cells (hPSCs), arranged them into 3D co-cultures within supportive gel matrices, and directed their propensity for self-organization resembling microvasculature. The resulting vascular cell populations and co-cultured constructs were then arrayed in high throughput and used for screening a library of environmental and clinical chemical agents for immunological and toxicological responses. The screen effectively stratified the chemicals into various levels of toxicity, with both cell type-specific and co-culture-dependent responses observed. Thus, hPSC-derived vascular cells and constructs could be progressed further toward use in toxicant and drug screening.
MeSH term(s)	Animals ; Cell Differentiation/drug effects ; Coculture Techniques ; Dose-Response Relationship, Drug ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; High-Throughput Screening Assays ; Humans ; Models, Biological ; Myocytes, Smooth Muscle/cytology ; Myocytes, Smooth Muscle/drug effects ; Myocytes, Smooth Muscle/metabolism ; Neovascularization, Physiologic/drug effects ; Neovascularization, Physiologic/physiology ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/drug effects ; Pluripotent Stem Cells/metabolism ; Small Molecule Libraries/toxicity
Chemical Substances	Small Molecule Libraries
Language	English
Publishing date	2019-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2142214-X
ISSN	1557-8534 ; 1547-3287
ISSN (online)	1557-8534
ISSN	1547-3287
DOI	10.1089/scd.2018.0246
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Article ; Online: Bringing Heparan Sulfate Glycomics Together with Proteomics for the Design of Novel Therapeutics: A Historical Perspective.

Nurcombe, Victor / Ling, Ling / Hondermarck, Hubert / Cool, Simon M / Smith, Raymond A A

Proteomics

2019 Volume 19, Issue 21-22, Page(s) e1800466

Abstract: Increasing knowledge of how peptides bind saccharides, and of how saccharides bind peptides, is starting to revolutionize understanding of cell-extracellular matrix relationships. Here, a historical perspective is taken of the relationship between ... ...

Abstract	Increasing knowledge of how peptides bind saccharides, and of how saccharides bind peptides, is starting to revolutionize understanding of cell-extracellular matrix relationships. Here, a historical perspective is taken of the relationship between heparan sulfate glycosaminoglycans and how they interact with peptide growth factors in order to both drive and modulate signaling through the appropriate cognate receptors. Such knowledge is guiding the preparation of targeted sugar mimetics that will impact the treatment of many different kinds of diseases, including cancer.
MeSH term(s)	Extracellular Matrix/genetics ; Glycomics ; Glycosaminoglycans/genetics ; Heparitin Sulfate/genetics ; Humans ; Neoplasms/genetics ; Peptides/genetics ; Protein Binding/genetics ; Proteomics ; Signal Transduction/genetics
Chemical Substances	Glycosaminoglycans ; Peptides ; Heparitin Sulfate (9050-30-0)
Language	English
Publishing date	2019-07-03
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2032093-0
ISSN	1615-9861 ; 1615-9853
ISSN (online)	1615-9861
ISSN	1615-9853
DOI	10.1002/pmic.201800466
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