Transcriptomic Analysis of Insulin-Secreting Murine Hepatocytes Transduced with an Integrating Adeno-Associated Viral Vector

Mahoney, ALG; Joshua, S; Nassif, NT; Simpson, AM

Transcriptomic Analysis of Insulin-Secreting Murine Hepatocytes Transduced with an Integrating Adeno-Associated Viral Vector

Mahoney, ALG Joshua, S

Nassif, NT Simpson, AM

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Publisher:: MDPI
Publication Type:: Journal Article
Citation:: International Journal of Translational Medicine, 3, (3), pp. 374-388

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Field	Value	Language
dc.contributor.author	Mahoney, ALG
dc.contributor.author	Joshua, S https://orcid.org/0000-0002-7954-2528
dc.contributor.author	Nassif, NT
dc.contributor.author	Simpson, AM
dc.date.accessioned	2023-12-05T04:39:12Z
dc.date.available	2023-12-05T04:39:12Z
dc.identifier.citation	International Journal of Translational Medicine, 3, (3), pp. 374-388
dc.identifier.issn	2673-8937
dc.identifier.issn	2673-8937
dc.identifier.uri	http://hdl.handle.net/10453/173708
dc.description.abstract	<jats:p>Type 1 Diabetes (T1D) is a chronic metabolic disorder for which current treatments are unable to prevent the onset of complications. Previously, we used an adeno-associated viral vector (AAV8) to deliver furin-cleavable human insulin (INS-FUR) to the livers of diabetic non-obese diabetic (NOD) mice to reverse T1D. The use of the traditional AAV8-INS-FUR vector could not bring about normoglycemia. However, this vector, coupled with a transposon system in the AAV8/piggyBac-INS-FUR vector, was able to do so. This study aimed to investigate the transcriptomic profiles of the livers of diabetic, AAV8-INS-FUR-transduced, and AAV8/piggyBac-INS-FUR-transduced NOD mice and compare these to the normal liver to identify genetic differences resulting from delivery of the AAV8/piggyBac-INS-FUR vector which produced normoglycemia. Differential gene expression was determined by RNA-Seq analysis and differentially expressed genes from each treatment were mapped onto cellular pathways to determine the treatments’ cell signaling and downstream effects. We observed distinct differences between the piggyBac-transduced and diabetic models, particularly in terms of metabolic function and the upregulation of key pancreatic markers in the liver of piggyBac-transduced animals. The success of the AAV8/piggyBac-INS-FUR vector in achieving normoglycemia through stable transduction was evident. However, further engineering is necessary to achieve complete pancreatic transdifferentiation of liver cells.</jats:p>
dc.language	en
dc.publisher	MDPI
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1187040
dc.relation	http://purl.org/au-research/grants/nhmrc/1086256
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1187040
dc.relation	http://purl.org/au-research/grants/nhmrc/GNT1086256
dc.relation.ispartof	International Journal of Translational Medicine
dc.relation.isbasedon	10.3390/ijtm3030026
dc.rights	info:eu-repo/semantics/openAccess
dc.title	Transcriptomic Analysis of Insulin-Secreting Murine Hepatocytes Transduced with an Integrating Adeno-Associated Viral Vector
dc.type	Journal Article
utslib.citation.volume	3
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.date.updated	2023-12-05T04:39:11Z
pubs.issue	3
pubs.publication-status	Published online
pubs.volume	3
utslib.citation.issue	3

Abstract:

Type 1 Diabetes (T1D) is a chronic metabolic disorder for which current treatments are unable to prevent the onset of complications. Previously, we used an adeno-associated viral vector (AAV8) to deliver furin-cleavable human insulin (INS-FUR) to the livers of diabetic non-obese diabetic (NOD) mice to reverse T1D. The use of the traditional AAV8-INS-FUR vector could not bring about normoglycemia. However, this vector, coupled with a transposon system in the AAV8/piggyBac-INS-FUR vector, was able to do so. This study aimed to investigate the transcriptomic profiles of the livers of diabetic, AAV8-INS-FUR-transduced, and AAV8/piggyBac-INS-FUR-transduced NOD mice and compare these to the normal liver to identify genetic differences resulting from delivery of the AAV8/piggyBac-INS-FUR vector which produced normoglycemia. Differential gene expression was determined by RNA-Seq analysis and differentially expressed genes from each treatment were mapped onto cellular pathways to determine the treatments’ cell signaling and downstream effects. We observed distinct differences between the piggyBac-transduced and diabetic models, particularly in terms of metabolic function and the upregulation of key pancreatic markers in the liver of piggyBac-transduced animals. The success of the AAV8/piggyBac-INS-FUR vector in achieving normoglycemia through stable transduction was evident. However, further engineering is necessary to achieve complete pancreatic transdifferentiation of liver cells.

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