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Differential chondrogenic differentiation between iPSC-derived from healthy and OA cartilage is associated with changes in epigenetic regulation and metabolic transcriptomic signatures

View ORCID ProfileNazir M. Khan, Martha Elena Diaz-Hernandez, Samir Chihab, Priyanka Priyadarshani, Pallavi Bhattaram, View ORCID ProfileLuke J. Mortensen, Rosa M Guzzo, Hicham Drissi
doi: https://doi.org/10.1101/2022.10.14.512213
Nazir M. Khan
1Department of Orthopaedics, Emory University, Atlanta, GA, USA
2Atlanta VA Medical Center, Decatur, GA, USA
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  • ORCID record for Nazir M. Khan
Martha Elena Diaz-Hernandez
1Department of Orthopaedics, Emory University, Atlanta, GA, USA
2Atlanta VA Medical Center, Decatur, GA, USA
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Samir Chihab
1Department of Orthopaedics, Emory University, Atlanta, GA, USA
2Atlanta VA Medical Center, Decatur, GA, USA
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Priyanka Priyadarshani
3School of Chemical Materials and Biomedical Engineering, University of Georgia, Athens, GA
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Pallavi Bhattaram
1Department of Orthopaedics, Emory University, Atlanta, GA, USA
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Luke J. Mortensen
3School of Chemical Materials and Biomedical Engineering, University of Georgia, Athens, GA
4Regenerative Bioscience Center, E.L. Rhodes Center for ADS, University of Georgia, Athens, GA
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Rosa M Guzzo
5Department of Neuroscience, School of Medicine, University of Connecticut Health, Farmington, CT, USA
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Hicham Drissi
1Department of Orthopaedics, Emory University, Atlanta, GA, USA
2Atlanta VA Medical Center, Decatur, GA, USA
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  • For correspondence: hicham.drissi@emory.edu
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ABSTRACT

Induced pluripotent stem cells (iPSCs) are potential cell sources for regenerative medicine. The iPSCs exhibit a preference for lineage differentiation to the donor cell type indicating the existence of memory of origin. Although the intrinsic effect of the donor cell type on differentiation of iPSCs is well recognized, whether disease-specific factors of donor cells influence the differentiation capacity of iPSC remains unknown. Using viral based reprogramming, we demonstrated the generation of iPSCs from chondrocytes isolated from healthy (AC-iPSCs) and osteoarthritis cartilage (OA-iPSCs). These reprogrammed cells acquired markers of pluripotency and differentiated into uncommitted-mesenchymal progenitors. Interestingly, AC-iPSCs exhibited enhanced chondrogenic potential as compared OA-iPSCs and showed increased expression of chondrogenic genes. Pan-transcriptome analysis showed that chondrocytes derived from AC-iPSCs were enriched in molecular pathways related to energy metabolism and epigenetic regulation, together with distinct expression signature that distinguishes them from OA-iPSCs. The molecular tracing data demonstrated that epigenetic and metabolic marks were imprint of original cell sources from healthy and OA-chondrocytes. Our results suggest that the epigenetic and metabolic memory of disease may predispose OA-iPSCs for their reduced chondrogenic differentiation and thus regulation at epigenetic and metabolic level may be an effective strategy for controlling the chondrogenic potential of iPSCs.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 14, 2022.
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Differential chondrogenic differentiation between iPSC-derived from healthy and OA cartilage is associated with changes in epigenetic regulation and metabolic transcriptomic signatures
Nazir M. Khan, Martha Elena Diaz-Hernandez, Samir Chihab, Priyanka Priyadarshani, Pallavi Bhattaram, Luke J. Mortensen, Rosa M Guzzo, Hicham Drissi
bioRxiv 2022.10.14.512213; doi: https://doi.org/10.1101/2022.10.14.512213
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Differential chondrogenic differentiation between iPSC-derived from healthy and OA cartilage is associated with changes in epigenetic regulation and metabolic transcriptomic signatures
Nazir M. Khan, Martha Elena Diaz-Hernandez, Samir Chihab, Priyanka Priyadarshani, Pallavi Bhattaram, Luke J. Mortensen, Rosa M Guzzo, Hicham Drissi
bioRxiv 2022.10.14.512213; doi: https://doi.org/10.1101/2022.10.14.512213

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