Retracted: Endothelial/Mesenchymal Stem Cell Crosstalk Within Bioprinted Cocultures
Authors: John P Fisher
Tolulope O Awosika
Max J Lerman
Marco Santoro
Amelia C Hurley-Novatny
Kirstie L Snodderly
Journal: Tissue Engineering Part A (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: bioprinting; coculture models; endothelial cells; mesenchymal stem cells.
Affiliations: Fischell Department of Bioengineering, University of Maryland, College Park, Maryland., Center for Engineering Complex Tissues, University of Maryland, College Park, Maryland., Department of Materials Science and Engineering, University of Maryland, College Park, Maryland.

Abstract:  The development of viable tissue surrogates requires a vascular network that sustains cell metabolism and tissue development. The coculture of endothelial cells (ECs) and mesenchymal stem cells (MSCs), the two key players involved in blood vessel formation, has been heralded in tissue engineering (TE) as one of the most promising approaches for scaffold vascularization. However, MSCs may exert both proangiogenic and antiangiogenic role. Furthermore, it is unclear which cell type is responsible for the upregulation of angiogenic pathways observed in EC:MSC cocultures. There is disagreement on the proangiogenic action of MSCs, as they have also been shown to negatively affect the formation of capillary networks. To address these issues, we investigated the regulation of key angiogenic pathways in scaffolds hosting different EC:MSC ratios fabricated through extrusion-based bioprinting. Human ECs were cocultured with either rat or human MSCs, and the regulation of fundamental angiogenic and arteriogenic pathways was analyzed through DNA, gene, and protein expression. The use of a hybrid human/rat coculture system facilitated pinpointing each cell type role in the regulation of specific genes and showed that MSCs exert a dose-dependent inhibitory effect on the EC expression of angiogenic factors within the first 24 h. Within a week of coculture, MSCs exert a proangiogenic effect, as corroborated in human/human bioprinted cocultures. Interestingly, juxtacrine signaling promoted secretion of the angiogenic factor vascular endothelial growth factor in direct cocultures (EC and MSC co-encapsulated), while paracrine signaling encouraged secretion of the arteriogenic factor platelet-derived growth factor in indirect cocultures (adjacent bioprinting of EC-laden and MSC-laden scaffolds). Overall, the use of a bioprinted system to elucidate EC:MSC interplay allows rapid leveraging of the data for novel vascular TE applications. Despite the transitory negative effect early in the culture, MSC presence is necessary for the regulation of pathways involved in arteriogenesis. With further validation in vivo, this study provides a possible explanation to the controversial findings present in literature and shows how MSC effect on angiogenic pathway regulation mimics the dynamics of blood vessel formation reported in literature and normally occurring in vivo. Impact Statement The coculturing of endothelial cells (ECs) and mesenchymal stem cells (MSCs) holds great promise in tissue engineering for the development of prevascularized tissue constructs. Yet, different studies report conflicting results on the role of MSCs, which can either support or inhibit vasculature formation. Furthermore, it is unclear how each cell type modulates distinct pathways involved in angiogenesis when cocultured. Using bioprinted hybrid coculture systems, we show that MSCs have both a time- and dose-dependent effect on the gene and protein expression of key angiogenic and arteriogenic factors by ECs. These findings, obtained in translationally relevant setup, can readily inform the design of vascularized scaffolds. 

Retracted: Yes

PubPeer comments:
 2020 retraction. https: www.liebertpub.com doi 10.1089 ten.tea.2019.0175.retract After publication of the article, one of the coauthors of the paper discovered a potential flaw in the analysis that was thought to be dispatched prior to the submission of the paper to Tissue Engineering Part A but was not. One of the co-editors of Tissue Engineering, John P. Fisher, PhD, is named as the senior author on the paper. Dr. Fisher has expressed deep regret about this error, and in the best interest of the scientific community and the readership of Tissue Engineering, has displayed rectitude in requesting the official retraction of his own article. Additionally, Dr. Fisher and his laboratory have strengthened the internal review processes of data collection and analysis so as to ensure that a similar error does not occur again in the future. Tissue Engineering remains committed to preserving the integrity of the scientific literature and the community it serves. ,